Compositions and methods of use for treating aberrant inflammation in peri-ocular secretory glands or at the ocular suface

ABSTRACT

Provided herein are pharmaceutical compositions comprising a therapeutically effective amount of a lipophilic compound and a pharmaceutically acceptable carrier adapted for pen-ocular transdermal delivery of the lipophilic compound to one or more periorbital glands and/or the ocular surface tissues of a subject. Further provided herein are methods of using such pharmaceutical compositions for providing relief of one or more signs or symptoms of an ocular disease, methods of using one or more Meibomian glands (and meibum therein) as a drug delivery system for a lipophilic compound (e.g., a steroid) to the ocular surface, and kits related thereto.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/US2018/062298, filed Nov. 21, 2018, which claims priority fromU.S. provisional application 62/589,493, filed Nov. 21, 2017, thecontents of which are incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present disclosure relates to pharmaceutical compositions adaptedfor peri-ocular transdermal delivery of one or more lipophiliccompounds; to methods of use thereof; and to kits comprising suchpharmaceutical compositions.

BACKGROUND

Topical drops have become the delivery method of choice for eye-carepractitioners especially for diseases like dry eye, uveitis, bacterialconjunctivitis, and glaucoma because the ocular surface is seen as theprimary target tissue for drug delivery. When a drop hits the eye, threeparts of the anterior segment (i.e., cornea, conjunctiva, and sclera)act as routes for the drug's absorption with the cornea representing theprimary route for ocular penetration. Drops are perceived as havingsignificant advantages over other methods of delivery, including theminimization of adverse systemic effects as well as the avoidance offirst-pass metabolism, which restricts the concentration of drug thatultimately reaches the target tissue (Abelson et al, 2012).

Topical eye drops, however, have several shortcomings: 1) They aredifficult for patients to physically manage; 2) There are physical andphysiological barriers that protect the eye and significantly diminishthe amount of drug being delivered (e.g., low corneal permeability,blinking reflex, and tear turnover); and 3) Epithelial tight junctionsprevent diffusion of larger molecules.

The lacrimal glands are paired, exocrine glands, one for each eye. Theyare located in the upper lateral region of each orbit, in the lacrimalfossa formed by the frontal bone. The lacrimal gland is the maincontributor to the aqueous layer of the tear film. The meibomian glandsare sebaceous glands in the eyelids inside the tarsal plate, responsiblefor the supply of meibum that prevents evaporation of the eye's tearfilm.

Disruption of the normal function of lacrimal and meibomian glands canresult in aqueous deficient and/or evaporative forms of dry eye disease(DED), as well as a whole host of “plus” inflammatory eye diseases, suchas exacerbated inflammatory ocular surface disease, phlyctenularkeratitis, chalazion, and anterior blepharitis (See e.g., the Tear Filmand Ocular Surface Society 2011 report on meibomian gland dysfunction(MGD); Nichols et al., 2011). Dry eye disease is a multifactorialdisease of the ocular surface characterized by a loss of homeostasis ofthe tear film, and accompanied by ocular symptoms in which tear filminstability and hyperosmolarity, ocular surface inflammation and damage,and neuronal sensory abnormalities play etiological roles (Craig et al.,2017). No matter what initiates a patient's DED (e.g., allergic eyedisease, topical preservative toxicity, or xerophthalmia), patientseventually enter a chain of inflammatory events that perpetuate thedisease. This inflammatory response can infiltrate the glandsthemselves. Indeed, tear dysfunction occurs when the lacrimal functionalunit (LFU), composed of the tear secreting glands, the ocular surface,and the sensory and motor nerves which connect these tissues, is nolonger able to maintain a stable precorneal tear layer (Beuerman et al.,1998; Stern et al., 1998a; Stern et al., 1998b). Disease or dysfunctionof one or more components of the LFU may lead to an altered tear film.While the etiology of DED is multifactorial, significant evidencesupports the hypothesis that the signs and symptoms are driven byinflammation of one or more components of the LFU.

Corticosteroid pharmacology targets inflammatory mediators underlyingthe signs and symptoms of DED. A number of studies and reports supportthe short-term use of topical corticosteroid eye drops in the treatmentof patients with DED (Avunduk et al., 2003; DEWS, 2007; Pflugfelder etal., 1999; Yang et al., 2006). However, topical ocular corticosteroidsadministered as eye drops are generally recommended only for short-termuse, as prolonged use may result in adverse ocular events, includingelevated intraocular pressure (TOP), cataracts, and ocular infection(Becker, 1964; Bowling and Russell, 2011; Dinning, 1976).

While steroid ointments/creams are extensively prescribed to controllong term or chronic non-ophthalmic inflammatory conditions (due totheir low penetration/permeation), the long term use of current steroidointment/cream formulations on or near the eyes is strongly disfavored,as ophthalmic use of these formulations is likely to induce seriousadverse events, such as increased TOP (which may result in ocularhypertension or glaucoma, or induce loss of sight), posteriorsubcapsular cataracts, retardation of corneal epithelial healing,corticosteroid uveitis, mydriasis and ptosis, infection, and otherpossible side effects (e.g., transient ocular discomfort,steroid-induced calcium deposits, etc.). In fact, topical application ofa typical dexamethasone ointment formulation to the eyelids of childrenwas shown to sharply increase IOP. “Ocular hypertensive response afterdexamethasone ointment to the eyelids occurred frequently in children,especially those 5 years old or younger” (See page 166 of Lee et al.,Korean J Ophthalmol. 2006 September; 20(3):166-70). Thus, steroidformulations/routes of administration appropriate for the long term oreven chronic therapy of inflammatory conditions of the eye are lacking.

All references cited herein, including patent applications, patentpublications, and non-patent literature are herein incorporated byreference in their entirety, as if each individual reference werespecifically and individually indicated to be incorporated by reference.

BRIEF SUMMARY

To meet the above and other needs, disclosed herein are pharmaceuticalcompositions adapted for pen-ocular transdermal delivery of one or morelipophilic compounds. In some embodiments, the pharmaceuticalcompositions are adapted for peri-ocular transdermal delivery tosignificantly enhance the ocular safety of the delivered lipophiliccompound by: 1) decreasing the concentration of the permeation enhancerin the pharmaceutical composition relative to the concentration used ina standard ointment/cream or ophthalmic formulation; 2) using apermeation enhancer (not typically found in topical steroidointment/cream formulations) that is suitable for transdermal deliveryof the compound into the eyelid (e.g., Tween-80); 3) formulating thepharmaceutical composition to achieve improved spreadability on theperi-ocular surface relative to an ointment base; 4) formulating thepharmaceutical composition to avoid flow from the pen-ocular surfaceonto the corneal surface; 5) using a novel steroid such as the compoundof Formula I (which has been specifically developed with an ability toenable the glucocorticoid receptor to transrepress gene activation withless or little transactivation) in an effort to reduce the side effectsof glucocorticoids that are thought to be mediated throughtransactivation; 6) using the Meibomian glands, meibum, and other fattystructures in the eyelids as a drug depot of a lipophilic compound forsustained delivery to the ocular surface; and/or 7) use of the Meibomianglands and meibum as a novel drug delivery system for a pharmaceuticalformulation of a lipophilic compound applied peri-ocularly to theoutside of the upper and/or lower eyelid(s). Accordingly, the presentdisclosure is directed, in part, to a safer method for treating ocularsurface conditions as well as within the peri-ocular glands and lids bytransdermally administering a pharmaceutical formulation (e.g., viatopical application of the formulation to the outside of the upperand/or lower eyelids) as described herein in order to deliver atherapeutically active concentration of a lipophilic compound to themeibomian glands, the lacrimal glands, the accessory lacrimal glands,and the ocular surface. Without wishing to be bound by theory it isthought that lipophilic compounds (e.g., steroids) will preferentiallyaccumulate in/partition to lipid-producing (e.g., meibum) pen-ocularglands (e.g., the Meibomian glands) and other fatty/lipophilicstructures in the eyelids. Consequently, the present disclosure isbelieved to provide a novel therapeutic strategy for treatinginflammation within the lacrimal functional unit (LFU), other ocularinflammatory diseases, bacterial infections of the eye, glaucoma, andocular hypertension by delivering anti-glaucoma agents, antibiotics andother lipophilic compounds via transdermal pen-ocular delivery thatdiminishes or avoids some or all of the adverse events associated withthe use of standard topical formulations in an ophthalmic setting, suchas increased TOP, BAK sensitivity, and disruption of the pre-cornealtear film (e.g., blurred vision). In addition, the present disclosure isbelieved to provide a novel strategy for longer term/chronic ophthalmictherapy than may be used with current short-term topical ocular regimens(e.g., corticosteroids).

Accordingly, in one aspect, provided herein are pharmaceuticalcompositions comprising a therapeutically effective amount of alipophilic compound, and a pharmaceutically acceptable carrier adaptedfor per-ocular transdermal delivery of the lipophilic compound to one ormore peri-orbital (e.g., oil-secreting peri-orbital) glands of asubject. In one aspect, provided herein are pharmaceutical compositionscomprising a therapeutically effective amount of a lipophilic compound,and a pharmaceutically acceptable carrier adapted for per-oculartransdermal delivery of the lipophilic compound to one or morepen-orbital (e.g., oil-secreting pen-orbital) glands of a subject,wherein the pharmaceutical composition is specifically formulated forperi-ocular delivery. In some embodiments, the lipophilic compound isnot delivered systemically to the subject. In some embodiments, thelipophilic compound is not delivered to a tear or tear duct of thesubject. In some embodiments, the lipophilic compound is not deliveredby direct application to an ocular surface of the subject. In someembodiments, the pharmaceutical composition is not a liquid topicalocular suspension, emulsion, or solution. In some embodiments, the oneor more peri-orbital glands are selected from the group consisting of ameibomian gland, a lacrimal gland, an accessory lacrimal gland, and anycombinations thereof. In some embodiments, the lipophilic compound isdelivered to an ocular surface of the subject via the meibomian glandand meibum. In some embodiments, the lipophilic compound is selectedfrom the group consisting of steroids, antibiotics, immunomodulatorydrugs, integrin antagonists, anti-inflammatory agents, and anti-glaucomaor ocular anti-hypertension agents.

In one aspect, provided herein are pharmaceutical compositionscomprising a therapeutically effective amount of a steroid, and apharmaceutically acceptable carrier adapted for per-ocular transdermaldelivery of the steroid to one or more peri-orbital (e.g., oil-secretingperi-orbital) glands of a subject. In some embodiments, thepharmaceutical composition is specifically formulated for peri-oculardelivery. In some embodiments, the steroid is not delivered systemicallyto the subject. In some embodiments, the steroid is not delivered to atear or tear duct of the subject. In some embodiments, the steroid isnot delivered by direct application to an ocular surface of the subject.In some embodiments, the pharmaceutical composition is not a liquidtopical ocular suspension, emulsion, or solution. In some embodiments,the one or more peri-orbital glands are selected from the groupconsisting of a meibomian gland, a lacrimal gland, an accessory lacrimalgland, and any combinations thereof. In some embodiments, the steroid isdelivered to an ocular surface of the subject via the meibomian glandand meibum.

The steroid can be any steroid. In some embodiments that may be combinedwith any of the preceding embodiments, the steroid is selected from thecompound of Formula I, fluocinolone, difluprednate, fluticasone,fluorometholone, loteprednol, dexamethasone, prednisolone, triamcinoloneacetonide, rimexolone, cortisol, cortisone, hydrocortisone,testosterone, and ester derivatives thereof. In some embodiments, thesteroid is selected from the compound of Formula I, difluprednate,loteprednol, dexamethasone, prednisolone, triamcinolone acetonide, andester derivatives thereof. In some embodiments, the steroid is thecompound of Formula I. In some embodiments, the pharmaceuticalcomposition comprises the steroid at a concentration between 0.001% and10% weight per weight (w/w). In some embodiments, the pharmaceuticalcomposition comprises the steroid at a concentration between 0.01% and2% w/w.

In one aspect, provided herein are pharmaceutical compositionscomprising a therapeutically effective amount of an antibiotic, and apharmaceutically acceptable carrier adapted for per-ocular transdermaldelivery of the antibiotic to one or more pen-orbital (e.g.,oil-secreting pen-orbital) glands of a subject. In one aspect, providedherein are pharmaceutical compositions comprising a therapeuticallyeffective amount of an antibiotic, and a pharmaceutically acceptablecarrier adapted for per-ocular transdermal delivery of the antibiotic toone or more pen-orbital (e.g., oil-secreting peri-orbital) glands of asubject, wherein the pharmaceutical composition is specificallyformulated for pen-ocular delivery. In some embodiments, the antibioticis not delivered systemically to the subject. In some embodiments, theantibiotic is not delivered to a tear or tear duct of the subject. Insome embodiments, the antibiotic is not delivered by direct applicationto an ocular surface of the subject. In some embodiments, thepharmaceutical composition is not a liquid topical ocular suspension,emulsion, or solution. In some embodiments, the one or more peri-orbitalglands are selected from the group consisting of a meibomian gland, alacrimal gland, an accessory lacrimal gland, and any combinationsthereof. In some embodiments, the antibiotic is delivered to an ocularsurface of the subject via the meibomian gland and meibum.

The antibiotic can be any antibiotic. In some embodiments, theantibiotic is selected from the group consisting of sulfonamides,macrolides, chloramphenicol, aminoglycosides, fluoroquinolones,vancomycin, and tetracyclines. In some embodiments, the antibiotic isselected from the group consisting of azithromycin, erythromycin,gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin,besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin,oxifloxacin, chloramphenicol, doxycycline, tetracyclin, gramicidin,mupirocin, polymyxin B, and sulfacetamide. In some embodiments, thepharmaceutical composition comprises the antibiotic at a concentrationbetween 0.01% and 10% weight per weight (w/w). In some embodiments, thepharmaceutical composition comprises the antibiotic at a concentrationbetween 0.1% and 2% w/w.

In one aspect, provided herein are pharmaceutical compositionscomprising a therapeutically effective amount of an immunomodulatorydrug, and a pharmaceutically acceptable carrier adapted for per-oculartransdermal delivery of the immunomodulatory drug to one or morepen-orbital (e.g., oil-secreting pen-orbital) glands of a subject. Inone aspect, provided herein are pharmaceutical compositions comprising atherapeutically effective amount of an immunomodulatory drug, and apharmaceutically acceptable carrier adapted for per-ocular transdermaldelivery of the immunomodulatory drug to one or more pen-orbital (e.g.,oil-secreting pen-orbital) glands of a subject, wherein thepharmaceutical composition is specifically formulated for pen-oculardelivery. In some embodiments, the immunomodulatory drug is notdelivered systemically to the subject. In some embodiments, theimmunomodulatory drug is not delivered to a tear or tear duct of thesubject. In some embodiments, the immunomodulatory drug is not deliveredby direct application to an ocular surface of the subject. In someembodiments, the pharmaceutical composition is not a liquid topicalocular suspension, emulsion, or solution. In some embodiments, the oneor more peri-orbital glands are selected from the group consisting of ameibomian gland, a lacrimal gland, an accessory lacrimal gland, and anycombinations thereof. In some embodiments, the immunomodulatory drug isdelivered to an ocular surface of the subject via the meibomian glandand meibum.

The immunomodulatory drug can be any immunomodulatory drug. In someembodiments, the immunomodulatory drug is selected from the groupconsisting of calcineurin inhibitors and thalidomide analogues. In someembodiments, the immunomodulatory drug is selected from the groupconsisting of cyclosporine A, voclosporine, tacrolimus, pimecrolimus,thalidomide, lenalidomide, and pomalidomide. In some embodiments, theimmunomodulatory drug is cyclosporine A. In some embodiments, thepharmaceutical composition comprises the immunomodulatory drug at aconcentration between 0.01% and 10% weight per weight (w/w). In someembodiments, the pharmaceutical composition comprises theimmunomodulatory drug at a concentration between 0.1% and 2% w/w.

In one aspect, provided herein are pharmaceutical compositionscomprising a therapeutically effective amount of an integrin antagonist,and a pharmaceutically acceptable carrier adapted for per-oculartransdermal delivery of the integrin antagonist to one or morepen-orbital (e.g., oil-secreting pen-orbital) glands of a subject. Inone aspect, provided herein are pharmaceutical compositions comprising atherapeutically effective amount of an integrin antagonist, and apharmaceutically acceptable carrier adapted for per-ocular transdermaldelivery of the integrin antagonist to one or more pen-orbital (e.g.,oil-secreting pen-orbital) glands of a subject, wherein thepharmaceutical composition is specifically formulated for pen-oculardelivery. In some embodiments, the integrin antagonist is not deliveredsystemically to the subject. In some embodiments, the integrinantagonist is not delivered to a tear or tear duct of the subject. Insome embodiments, the integrin antagonist is not delivered by directapplication to an ocular surface of the subject. In some embodiments,the pharmaceutical composition is not a liquid topical ocularsuspension, emulsion, or solution. In some embodiments, the one or moreperi-orbital glands are selected from the group consisting of ameibomian gland, a lacrimal gland, an accessory lacrimal gland, and anycombinations thereof. In some embodiments, the integrin antagonist isdelivered to an ocular surface of the subject via the meibomian glandand meibum.

The integrin antagonist can be any integrin antagonist. In someembodiments, the integrin antagonist is selected from the groupconsisting of lifitegrast and GW559090, and ester derivatives thereof.In some embodiments, the pharmaceutical composition comprises theintegrin antagonist at a concentration between 0.01% and 10% weight perweight (w/w). In some embodiments, the pharmaceutical compositioncomprises the integrin antagonist at a concentration between 0.1% and 5%w/w.

In one aspect, provided herein are pharmaceutical compositionscomprising a therapeutically effective amount of an anti-inflammatoryagent, and a pharmaceutically acceptable carrier adapted for per-oculartransdermal delivery of the anti-inflammatory agent to one or morepen-orbital (e.g., oil-secreting pen-orbital) glands of a subject. Inone aspect, provided herein are pharmaceutical compositions comprising atherapeutically effective amount of an anti-inflammatory agent, and apharmaceutically acceptable carrier adapted for per-ocular transdermaldelivery of the anti-inflammatory agent to one or more pen-orbital(e.g., oil-secreting pen-orbital) glands of a subject, wherein thepharmaceutical composition is specifically formulated for pen-oculardelivery. In some embodiments, the anti-inflammatory agent is notdelivered systemically to the subject. In some embodiments, theanti-inflammatory agent is not delivered to a tear or tear duct of thesubject. In some embodiments, the anti-inflammatory agent is notdelivered by direct application to an ocular surface of the subject. Insome embodiments, the pharmaceutical composition is not a liquid topicalocular suspension, emulsion, or solution. In some embodiments, the oneor more peri-orbital glands are selected from the group consisting of ameibomian gland, a lacrimal gland, an accessory lacrimal gland, and anycombinations thereof. In some embodiments, the anti-inflammatory agentis delivered to an ocular surface of the subject via the meibomian glandand meibum.

The anti-inflammatory agent can be any anti-inflammatory agent. In someembodiments, the anti-inflammatory agent is selected from the groupconsisting of omega 3 fatty acids and non-steroidal anti-inflammatorydrugs (NSAIDs). In some embodiments, the omega 3 fatty acids areselected from the group consisting of eicosapentaenoic acid (EPA),docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and anycombinations thereof. In some embodiments, the NSAIDs are selected fromthe group consisting of bromfenac, diclofenac, indomethacin,flurbiprofen, ketorolac, nepafenac, and any combinations thereof. Insome embodiments, the anti-inflammatory agent is selected fromflurbiprofen and ketorolac. In some embodiments, the pharmaceuticalcomposition comprises the anti-inflammatory agent at a concentrationbetween 0.001% and 10% weight per weight (w/w). In some embodiments, thepharmaceutical composition comprises the anti-inflammatory agent at aconcentration between 0.1% and 2% w/w.

In one aspect, provided herein are pharmaceutical compositionscomprising a therapeutically effective amount of an anti-glaucoma orocular anti-hypertension agent, and a pharmaceutically acceptablecarrier adapted for per-ocular transdermal delivery of the anti-glaucomaor ocular anti-hypertension agent to one or more pen-orbital (e.g.,oil-secreting pen-orbital) glands of a subject. In one aspect, providedherein are pharmaceutical compositions comprising a therapeuticallyeffective amount of an anti-glaucoma or ocular anti-hypertension agent,and a pharmaceutically acceptable carrier adapted for per-oculartransdermal delivery of the anti-glaucoma or ocular anti-hypertensionagent to one or more pen-orbital (e.g., oil-secreting pen-orbital)glands of a subject, wherein the pharmaceutical composition isspecifically formulated for peri-ocular delivery. In some embodiments,the anti-glaucoma or ocular anti-hypertension agent is not deliveredsystemically to the subject. In some embodiments, the anti-glaucoma orocular anti-hypertension agent is not delivered to a tear or tear ductof the subject. In some embodiments, the anti-glaucoma or ocularanti-hypertension agent is not delivered by direct application to anocular surface of the subject. In some embodiments, the pharmaceuticalcomposition is not a liquid topical ocular suspension, emulsion, orsolution. In some embodiments, the one or more peri-orbital glands areselected from the group consisting of a meibomian gland, a lacrimalgland, an accessory lacrimal gland, and any combinations thereof. Insome embodiments, the anti-glaucoma or ocular anti-hypertension agent isdelivered to an ocular surface of the subject via the meibomian glandand meibum.

The anti-glaucoma or ocular anti-hypertension agent can be anyanti-glaucoma agent or any ocular anti-hypertension agent. In someembodiments, the anti-glaucoma or ocular anti-hypertension agent isselected from the group consisting of bimatoprost, latanoprost,travoprost, tafluprost, latanoprostene-bunod, timolol, betaxolol,levobunolol, dorzolamide, brinzolamide, and acetazolamide. In someembodiments, the anti-glaucoma or ocular anti-hypertension agent isselected from bimatoprost, latanoprost, travoprost, tafluprost,latanoprostene-bunod, timolol, betaxolol, levobunolol, metipranolol,brimonidine, clonidine, apraclonidine, dorzolamide, brinzolamide,acetazolamide, methazolamide, netarsudil, and any combinations thereof.In some embodiments the anti-glaucoma drug is selected from bimatoprost,latanoprost, travoprost, brimonidine, brinzolamide, netarsudil andtimolol. In some embodiments the anti-glaucoma agent is bimatoprost. Insome embodiments, the pharmaceutical composition comprises theanti-glaucoma drug at a concentration between 0.0001% and 10% weight perweight (w/w). In some embodiments, the pharmaceutical compositioncomprises the anti-glaucoma drug or ocular anti-hypertension agent at aconcentration between 0.01% and 2% w/w.

In some embodiments that may be combined with any of the precedingembodiments, the pharmaceutical composition further comprises atherapeutically effective amount of an additional steroid. In someembodiments, the additional steroid is selected from the compound ofFormula I, fluocinolone, difluprednate, fluticasone, fluorometholone,loteprednol, dexamethasone, prednisolone, triamcinolone acetonide,rimexolone, cortisol, cortisone, hydrocortisone, testosterone, and esterderivatives thereof. In some embodiments, the lipophilic compound andthe additional steroid are different.

In some embodiments that may be combined with any of the precedingembodiments, the pharmaceutical composition further comprises atherapeutically effective amount of one or more antibiotics. In someembodiments, the one or more antibiotics are selected from sulfonamides,macrolides, chloramphenicol, aminoglycosides, fluoroquinolones,vancomycin, tetracyclines, and any combinations thereof. In someembodiments, the one or more antibiotics are selected from azithromycin,erythromycin, gentamicin, natamycin, neomycin, tobramycin, vancomycin,bacitracin, besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin,moxifloxacin, oxifloxacin, chloramphenicol, doxycycline, tetracyclin,gramicidin, mupirocin, polymyxin B, sulfacetamide, and any combinationsthereof. In some embodiments, the one or more antibiotics are selectedfrom azithromycin, gentamicin, tobramycin, bacitracin, besifloxacin,gatifloxacin, moxifloxacin, chloramphenicol, and doxycycline. In someembodiments, the pharmaceutical composition comprises the one or moreantibiotics at a concentration between 0.01% and 10% weight per weight(w/w). In some embodiments, the pharmaceutical composition comprises theone or more antibiotics at a concentration between 0.1% and 2% w/w. Insome embodiments, the lipophilic compound and the one or moreantibiotics are different.

In some embodiments that may be combined with any of the precedingembodiments, the pharmaceutical composition further comprises atherapeutically effective amount of one or more immunomodulatory drugs.In some embodiments, the one or more immunomodulatory drugs are selectedfrom calcineurin inhibitors, thalidomide analogues, and any combinationsthereof. In some embodiments, the one or more immunomodulatory drugs areselected from cyclosporine A, voclosporine, tacrolimus, pimecrolimus,thalidomide, lenalidomide, pomalidomide, and any combinations thereof.In some embodiments, the immunomodulatory drug is cyclosporine A. Insome embodiments, the pharmaceutical composition comprises the one ormore immunomodulatory drugs at a concentration between 0.01% and 10%weight per weight (w/w). In some embodiments, the pharmaceuticalcomposition comprises the one or more immunomodulatory drugs at aconcentration between 0.1% and 2% w/w. In some embodiments, thelipophilic compound and the one or more immunomodulatory drugs aredifferent.

In some embodiments that may be combined with any of the precedingembodiments, the pharmaceutical composition further comprises atherapeutically effective amount of one or more integrin antagonists. Insome embodiments, the one or more integrin antagonists are selected fromlifitegrast, GW559090, ester derivatives thereof, and any combinationsthereof. In some embodiments, the integrin antagonist is GW559090. Insome embodiments, the pharmaceutical composition comprises the one ormore integrin antagonists at a concentration between 0.01% and 10%weight per weight (w/w). In some embodiments, the pharmaceuticalcomposition comprises the one or more integrin antagonists at aconcentration between 0.1% and 5% w/w. In some embodiments, thelipophilic compound and the one or more integrin antagonists aredifferent.

In some embodiments that may be combined with any of the precedingembodiments, the pharmaceutical composition further comprises atherapeutically effective amount of one or more anti-inflammatoryagents. In some embodiments, the one or more anti-inflammatory agentsare selected from omega 3 fatty acids, non-steroidal anti-inflammatorydrugs (NSAIDs), and any combinations thereof. In some embodiments, theomega 3 fatty acids are selected from eicosapentaenoic acid (EPA),docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), and anycombinations thereof. In some embodiments, the NSAIDs are selected frombromfenac, diclofenac, indomethacin, flurbiprofen, ketorolac, nepafenac,and any combinations thereof. In some embodiments, the one or moreanti-inflammatory agents is selected from flurbiprofen and ketorolac. Insome embodiments, the pharmaceutical composition comprises the one ormore anti-inflammatory agents at a concentration between 0.001% and 10%weight per weight (w/w). In some embodiments, the pharmaceuticalcomposition comprises the one or more anti-inflammatory agents at aconcentration between 0.1% and 2% w/w. In some embodiments, thelipophilic compound and the one or more anti-inflammatory agents aredifferent.

In some embodiments that may be combined with any of the precedingembodiments, the pharmaceutical composition further comprises atherapeutically effective amount of one or more anti-glaucoma drugs orocular anti-hypertension agents. In some embodiments, the one or moreanti-glaucoma drugs or ocular anti-hypertension agents are selected frombimatoprost, latanoprost, travoprost, tafluprost, latanoprostene-bunod,timolol, betaxolol, levobunolol, metipranolol, brimonidine, clonidine,apraclonidine, dorzolamide, brinzolamide, acetazolamide, methazolamide,netarsudil, and any combinations thereof. In some embodiments theanti-glaucoma drug or ocular anti-hypertension agent is selected frombimatoprost, latanoprost, travoprost, brimonidine, brinzolamide,netarsudil and timolol. In some embodiments the anti-glaucoma drug isbimatoprost. In some embodiments, the pharmaceutical compositioncomprises the one or more anti-glaucoma drugs or ocularanti-hypertension agents at a concentration between 0.0001% and 10%weight per weight (w/w). In some embodiments, the pharmaceuticalcomposition comprises the one or more anti-glaucoma drugs or ocularanti-hypertension agents at a concentration between 0.01% and 2% w/w. Insome embodiments, the lipophilic compound and the one or moreanti-glaucoma drugs or ocular anti-hypertension agents are different.

In some embodiments that may be combined with any of the precedingembodiments, the pharmaceutically acceptable carrier is selected from anointment, cream, lotion, gel, emulsion, suspension, oil, foam,transdermal patch, spray, and any combinations thereof. In someembodiments, the pharmaceutically acceptable carrier is an ointment. Insome embodiments, the ointment comprises a paraffinic or awater-miscible ointment base. In some embodiments, the ointmentcomprises 61.5% w/w white soft paraffin, 8% w/w mineral oil, 8% w/wpropylene glycol, 5% w/w of St. cyclomethicone-SNF, 5% w/w of labrasol,5% w/w of propylene carbonate, 2.5% w/w of steareth 2, 2.5% w/w of St.emulsifier 10, and 2.5% w/w of St. elastomer-10. In some embodiments,the pharmaceutically acceptable carrier is a cream. In some embodiments,the cream comprises an oil-in-water base or a water-in-oil base. In someembodiments, the cream comprises 48% w/w soft paraffin, 8% w/w mineraloil, 8% w/w propylene glycol, 6.6% w/w ST-cyclomethicone-SNF, 3.3% w/wST-emulsifier-10, 2% w/w ST-elastomer-10, 0.08% w/w methylparaben, 0.06%w/w dibasic sodium phosphate, 0.05% w/w citric acid, 0.02% w/wpropylparaben, and q.s. purified water. In some embodiments, the creamcomprises 48% w/w white petrolatum, 8% w/w mineral oil, 8% w/w propyleneglycol, 6.6% w/w ST-cyclomethicone-SNF, 3.3% w/w emulsifier 10, 2% w/wST-elastomer-10, 0.08% w/w methylparaben, 0.06% w/w sodium phosphatedibasic anhydrous, 0.05% w/w citric acid anhydrous, 0.02% w/wpropylparaben, and q.s. purified water. In some embodiments, the creamcomprises 48% w/w white petrolatum, 8% w/w mineral oil, 8% w/w propyleneglycol, 6.6% w/w ST-cyclomethicone-SNF, 3.3% w/w emulsifier 10, 2% w/wST-elastomer-10, 0.06% w/w sodium phosphate dibasic anhydrous, 0.05% w/wcitric acid anhydrous, 0.02% w/w benzalkonium chloride, and q.s.purified water. In some embodiments, the cream is preservative-freecomprising 48% w/w white petrolatum, 8% w/w mineral oil, 8% w/wpropylene glycol, 6.6% w/w ST-cyclomethicone-SNF, 3.3% w/w emulsifier10, 2% w/w ST-elastomer-10, 0.06% w/w sodium phosphate dibasicanhydrous, 0.05% w/w citric acid anhydrous, and q.s. purified water.

In some embodiments, one or more active pharmaceutical ingredients areincorporated at the desired final concentration (w/w) into a creamvehicle comprised of 48% w/w white petrolatum, 8% w/w mineral oil, 8%w/w propylene glycol, 6.6% w/w ST-cyclomethicone-SNF, 3.3% w/wemulsifier 10, 2% w/w ST-elastomer-10, 0.08% w/w methylparaben, 0.06%w/w sodium phosphate dibasic anhydrous, 0.05% w/w citric acid anhydrous,0.02% w/w propylparaben, and q.s. purified water. In some embodiments,the cream vehicle comprises 48% w/w white petrolatum, 8% w/w mineraloil, 8% w/w propylene glycol, 6.6% w/w ST-cyclomethicone-SNF, 3.3% w/wemulsifier 10, 2% w/w ST-elastomer-10, 0.06% w/w sodium phosphatedibasic anhydrous, 0.05% w/w citric acid anhydrous, 0.02% w/wbenzalkonium chloride, and q.s. purified water. In some embodiments, thecream vehicle is preservative-free comprising 48% w/w white petrolatum,8% w/w mineral oil, 8% w/w propylene glycol, 6.6% w/wST-cyclomethicone-SNF, 3.3% w/w emulsifier 10, 2% w/w ST-elastomer-10,0.06% w/w sodium phosphate dibasic anhydrous, 0.05% w/w citric acidanhydrous, and q.s. purified water.

In some embodiments, one or more active pharmaceutical ingredients areincorporated at the desired final concentration by substituting an equalamount of white petrolatum or paraffin (w/w). As an example, one suchembodiment comprises 46% w/w white petrolatum, 8% w/w mineral oil, 8%w/w propylene glycol, 6.6% w/w ST-cyclomethicone-SNF, 3.3% w/wemulsifier 10, 2% w/w ST-elastomer-10, 0.08% w/w methylparaben, 0.06%w/w sodium phosphate dibasic anhydrous, 0.05% w/w citric acid anhydrous,0.02% w/w propylparaben, 2% w/w compound of Formula I and q.s. purifiedwater. Another such embodiment is preservative-free and comprises 46%w/w white petrolatum, 8% w/w mineral oil, 8% w/w propylene glycol, 6.6%w/w ST-cyclomethicone-SNF, 3.3% w/w emulsifier 10, 2% w/wST-elastomer-10, 0.06% w/w sodium phosphate dibasic anhydrous, 0.05% w/wcitric acid anhydrous, 2% w/w compound of Formula I and q.s. purifiedwater.

In some embodiments, the pharmaceutical composition comprises thelipophilic compound at a concentration between about 0.001% and about10% weight per weight (w/w), between about 0.0001% and about 10% weightper weight (w/w), or between about 0.0001% and about 5% weight perweight (w/w). In some embodiments, the pharmaceutical compositioncomprises the lipophilic compound at a concentration between about 0.01%and about 2% w/w.

In some embodiments, the pharmaceutically acceptable carrier comprisesbenzalkonium chloride (BAK). In some embodiments, the pharmaceuticallyacceptable carrier comprises 48% w/w white petrolatum, 8% w/w mineraloil, 8% w/w propylene glycol, 6.6% w/w ST-cyclomethicone-SNF, 3.3% w/wemulsifier 10, 2% w/w ST-elastomer-10, 0.06% w/w sodium phosphatedibasic anhydrous, 0.05% w/w citric acid anhydrous, 0.02% w/wbenzalkonium chloride, and purified water. In some embodiments, thepharmaceutically acceptable carrier is preservative-free. In someembodiments, the pharmaceutically acceptable carrier comprises whitesoft paraffin/petrolatum, mineral oil, propylene glycol,ST-cyclomethicone-SNF, ST-emulsifier-10, ST-elastomer-10, dibasic sodiumphosphate, citric acid, and purified water. In some embodiments, thepharmaceutically acceptable carrier comprises 48% w/w white petrolatum,8% w/w mineral oil, 8% w/w propylene glycol, 6.6% w/wST-cyclomethicone-SNF, 3.3% w/w emulsifier 10, 2% w/w ST-elastomer-10,0.06% w/w sodium phosphate dibasic anhydrous, 0.05% w/w citric acidanhydrous, and purified water.

In some embodiments that may be combined with any of the precedingembodiments, the subject is a human or a non-human animal. In someembodiments that may be combined with any of the preceding embodiments,the subject is suffering from, or is suspected and/or expected to besuffering from, inflammation of one or more peri-orbital glands. In someembodiments that may be combined with any of the preceding embodiments,the subject suffers from an ocular disease. In some embodiments, theocular disease is selected from inflammation of the peri-ocular glands,meibomitis, dry eye disease, allergic eye disease, topical preservativetoxicity, xerophthalmia, loss of homeostasis of the tear film, tear filminstability and hyperosmolarity, ocular surface inflammation and damage,neuronal sensory abnormalities, meibomian gland dysfunction, exacerbatedinflammatory ocular surface disease, phlyctenular keratitis, chalazion,anterior blepharitis, posterior blepharitis, bacterial infection,glaucoma, ocular hypertension, and any combinations thereof.

In another aspect, provided herein are methods of providing prophylacticpalliative, or therapeutic relief of one or more signs or symptoms of anocular disease in a subject comprising administering to the subject anyof the pharmaceutical compositions described herein. In someembodiments, the subject is a human or a non-human animal. In someembodiments, the subject is suffering from, or is suspected and/orexpected to be suffering from, inflammation of one or more peri-orbitalglands. In some embodiments, the subject suffers from an ocular disease.In some embodiments, the ocular disease is selected from inflammation ofthe pen-ocular glands, meibomitis, dry eye disease, allergic eyedisease, topical preservative toxicity, xerophthalmia, loss ofhomeostasis of the tear film, tear film instability and hyperosmolarity,ocular surface inflammation and damage, neuronal sensory abnormalities,meibomian gland dysfunction, exacerbated inflammatory ocular surfacedisease, phlyctenular keratitis, chalazion, anterior blepharitis,posterior blepharitis, bacterial infection, glaucoma, ocularhypertension, and any combinations thereof.

In some embodiments that may be combined with any of the precedingembodiments, the pharmaceutical composition is topically administered toan external portion of an eyelid of the subject, including the upperlateral region of an orbit of the subject. In some embodiments, thepharmaceutical composition is topically administered to the externalportion of the upper and/or lower eyelid of the subject. In someembodiments, the lipophilic compound is delivered to an ocular surfaceof the subject via the meibomian gland. In some embodiments, thepharmaceutical composition is administered one, two, three, four, five,six or more times per day. In some embodiments, the pharmaceuticalcomposition is administered for one day, two days, three days, fourdays, five days, six days, one week, two weeks, three weeks, four weeks,five weeks, six weeks, seven weeks, eight weeks, nine weeks, 10 weeks,11 weeks, 12 weeks or more, 24 weeks, 36 weeks, 48 weeks or more. Insome embodiments, prolonged administration of the pharmaceuticalcomposition does not result in an adverse ocular event in the subject.In some embodiments, the adverse ocular event is selected from elevatedintraocular pressure, cataracts, ocular infection, and any combinationsthereof. In some embodiments, the lipophilic compound is not deliveredsystemically to the subject by the administration of the pharmaceuticalcomposition. In some embodiments, the lipophilic compound is notdelivered to a tear or tear duct of the subject by the administration ofthe pharmaceutical composition. In some embodiments, the lipophiliccompound is not delivered directly to an ocular surface of the subjectby the administration of the pharmaceutical composition.

In another aspect, provided herein are articles of manufacture or kitscomprising any of the pharmaceutical compositions described herein. Insome embodiments, the article of manufacture or kit further comprises apackage insert comprising instructions for administering thepharmaceutical composition.

It is to be understood that one, some, or all of the properties of thevarious embodiments described above and herein may be combined to formother embodiments of the present disclosure. These and other aspects ofthe present disclosure will become apparent to one of skill in the art.These and other embodiments of the present disclosure are furtherdescribed by the detailed description that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the average diurnal intraocular pressure (TOP) during a4-week treatment period with the indicated treatments administeredtopically to the eye. Analysis was conducted by a mixed effects model onthe raw IOP data. Data are presented as the fitted IOP means±95%confidence limits; a * indicates a p<0.05, as compared to thedexamethasone-treated group.

FIG. 2 shows the change in tear formation during 7 days of topicalapplication of the indicated treatments. Repeated measures analysisfollowed by the Sidak's test; GW870086=compound of formula I; a *indicates a p<0.05, as compared to the atropine+vehicle-treated group.

FIG. 3A and FIG. 3B shows the physical rigidity of various cream samplesand a high viscosity standard equilibrated at 37° C. in glass vials andinverted for 5 minutes. Samples in FIG. 3A are 2% compound of Formula Icream (left), placebo cream (center), high viscosity polybutene standardN62000 (right); samples in FIG. 3B are 2% dexamethasone cream (vial C onleft), 2% loteprednol etabonate cream (vial B in center), 2%cyclosporine A cream (vial A on right). Sample deposition on the insideof the glass vial wall was not caused by sample flow but accidentaldeposition from the pipette during sample transfer to the vial. That didnot interfere with observation of flow or change in the meniscus withthermal treatment and inversion.

FIGS. 4A-D shows results of the step strain stress relaxationmeasurements for some of the samples; a) white petrolatum at 25° C.(FIG. 4A); b) white petrolatum at 37° C. (FIG. 4B); c) placebo cream at25° C. (FIG. 4C); d) 2% triamcinolone acetonide (sample K) cream at 25°C. (FIG. 4D).

FIG. 5 shows epidermal, dermal, and receptor fluid levels of thecompound of Formula I 46 hours after topical application to theepidermis of a 2% compound of Formula I cream. Results were obtainedfrom 6 replicates of an in vitro skin penetration study using humancadaver skin samples mounted in Franz Diffusion Cells; receptor fluidwas in contact with the dermis.

FIG. 6 shows ocular exposure levels in minipig eyes followingtwice-daily eyelid administration of a 2% compound of Formula I creamover 7.5 days. Time points are 2, 4, 8, and 24 hours after the finaldose on day 8.

FIG. 7 process flow chart for manufacturing of a cream comprising thecompound of Formula I.

DETAILED DESCRIPTION

Provided herein are pharmaceutical compositions comprising atherapeutically effective amount of a lipophilic compound, and apharmaceutically acceptable carrier adapted for pen-ocular transdermaldelivery of the lipophilic compound to one or more peri-orbital glands(e.g., the meibomian, lacrimal, and/or accessory lacrimal glands) of asubject. In some embodiments, the pharmaceutical composition isspecifically formulated for peri-ocular delivery in accordance with theteachings herein. Also provided herein are methods of providingprophylactic, palliative, and/or therapeutic relief of one or more signsor symptoms of an ocular disease (e.g., an ocular inflammatorycondition, bacterial infection, or glaucoma) comprising administering atherapeutically effective amount of any of the pharmaceuticalcompositions of the present disclosure to a subject in need thereof.Also provided herein are articles of manufacture or kits comprising oneor more of the pharmaceutical compositions described herein.

Topical drops have become the delivery method of choice for eye-carepractitioners especially for diseases like dry eye, uveitis, bacterialconjunctivitis, and glaucoma because the ocular surface is seen as theprimary target tissue for drug delivery. However, the eye's rapidturnover of tears creates a significant problem for an ocular drop. Thetear film is only about 7 μL in volume. An eye drop is about 30 to 50μL, depending on the surface tension characteristics of the drug;therefore, only up to 1 to 3 percent of an active pharmaceuticalingredient (API) in a topical drop penetrates to the intended targettissues in the eye. The remainder of the drop drains from the tear filmthrough the nasolacrimal system. Finally, the contact time of a drugwith the ocular tissues is only around one minute due to the constantproduction of lacrimal fluid (0.5 to 2.2 μl/min.) and drainage (Abelsonet al, 2012). Methods that increase a drug's retention time on thetreated eye include high-viscosity solutions (e.g., Tobradex ST) andnovel technologies such as mucous membrane penetrating technologies(e.g., Kala Pharmaceuticals, KPI-121), bioadhesive gels and fibrinsealant-based approaches (Gaudana R et al, 2010). Pen-ocular routes ofdelivery for ocular conditions include subconjunctival, subtenon,retrobulbar, and peribulbar administration (See FIG. 1 in Gaudana R etal, 2010).

Applying a drug directly to the eyelids has been envisioned as a routeof drug delivery for lid conditions such as Meibomian Gland Dysfunction(MGD) and blepharitis. Meibomian gland dysfunction (MGD) is a chronic,diffuse abnormality of the meibomian glands (which reside in theeyelids), commonly characterized by terminal duct obstruction and/orqualitative/quantitative changes in the glandular secretion (Nichols etal, 2011). Blepharitis is inflammation of the eyelids. Local liddelivery has been envisioned for diseases impacting the lids because asAbelson and colleagues (2012) stated, “When you want to treat a localcondition, the more local the delivery, the better the result will be.What better example of this need is there than the delivery oftherapeutics for blepharitis directly to the affected lids?”

MacKeen et al (1995) reported on a unique drug delivery system thatconsists of applying petrolatum ointment vehicle to the lower eyelid.The ointment melts at skin temperature and gradually moves over the skinonto the ocular surface. The movement of the petrolatum ointment wastermed supracutaneous. For this method to work, the musculature of thelower lid must move the drug toward and over the lid margin. Thus, thismethod of drug delivery envisions that the applied drug does notpenetrate the skin of the lower lid, but instead travels on the surfaceof the skin around the eyelid where it physically mixes with the tearfilm (see also Tsubota et al, 1999).

The pharmaceutical compositions and methodologies of the presentinvention are based upon the unexpected finding that, when properlyformulated in a suitable vehicle that, following topical pen-ocularapplication to one or both eyelids of an eye, does not melt and flow ormove onto the ocular surface, but, instead, penetrates into the eyelidalong with its API payload, lipophilic drugs delivered topically to thelids in such a manner can access the meibomian glands, meibum and otherfatty structures within the eyelids which themselves can act as a drugdepot resulting in sustained delivery to the ocular surface. Thus, “themore local the delivery, the better the result will be” is not anaccurate way to conceive of delivering a lipophilic compound to theocular surface. The current method of drug delivery also relies uponpenetration of the eyelid skin, which is inconsistent with prior artthat envisions the eyelid skin as a barrier to successful ocular surfacedrug delivery.

Commonly used lipophilic, topical, ocular therapeutics that couldbenefit from this new delivery method include treatments forinflammatory eye diseases, which include dry eye disease (e.g.,RESTASIS® and corticosteroids), glaucoma (e.g., latanoprost), andbacterial conjunctivitis (e. g. , AzaS ite).

Pflugfelder and colleagues (2004) demonstrated that a topicalcorticosteroid may achieve the objective of a short-term treatment ofacute exacerbations of DED signs or symptoms. They evaluated loteprednoletabonate ophthalmic suspension (0.5%) dosed 4 times daily versusplacebo for the treatment of DED in patients with delayed tearclearance. In patients with at least moderate clinical inflammation,significant differences in clinical signs (nasal and tarsal hyperemia)between groups were observed as early as week 2 and persisted throughweek 4 of the study. In addition, the improvement in the redness visualanalog scale (VAS) score was consistently 20% better in theloteprednol-treated patients compared with the vehicle-treated patients.

Capitalizing on the known safety profile of loteprednol etabonate, KalaPharmaceuticals, Inc is developing KPI-121 as a novel nanoparticleformulation of loteprednol etabonate using mucus-penetrating particle(MPP) technology. In October of 2017, Kala filed an IND for KPI-121 1%as a treatment for inflammation and pain following ocular surgery. InJanuary of 2018, they announced top line results for KPI-121 0.25% forthe temporary relief of the signs and symptoms of DED. Their two Phase 3DED studies (STRIDE 1 and STRIDE 2) demonstrated that KPI-121 0.25%dosed four-times-daily (QID) could provide statistically significantreductions in conjunctival hyperemia and marginal reductions in oculardiscomfort severity at Day 15. Their topical ocular route of deliveryresults in several significant challenges for the introduction of asuccessful treatment: 1) QID dosing is inconvenient for patients andlikely to result in poor compliance; 2) the need for frequentadministration to maintain therapeutically active drug levels foranti-inflammatory efficacy; 3) potential safety concerns related tofrequent administration; and 4) the need for a vehicle that can itselfalter the functional characteristics of a normal tear film.

In addition to seeking sustained release formulations for inflammatoryeye conditions to improve patient adherence by reducing dosing frequencyand increasing efficacy by establishing more sustained suppression ofinflammation, sustained release formulations are being developed inglaucoma to additionally remove preservatives such as benzalkoniumchloride (BAK) and for bacterial conjunctivitis to prevent periods ofregrowth. Thus, there is a need across ophthalmic conditions for asustained release formulation that is less invasive, reduces dosingfrequency, maintains constant therapeutic exposures at the site ofaction, minimizes disruption of the pre-corneal tear film, and reducesocular exposure to formulation excipients.

I. Pharmaceutical Compositions

Certain aspects of the present disclosure relate to a pharmaceuticalcomposition comprising a therapeutically effective amount of alipophilic compound, and a pharmaceutically acceptable carrier adaptedfor peri-ocular transdermal delivery of the lipophilic compound to oneor more peri-orbital glands (e.g., the meibomian, lacrimal, and/oraccessory lacrimal glands) of a subject. The term “peri-ocular” refersto the area surrounding the eyeball but within the orbit, includingeyelids and lateral regions of the orbit. The peri-orbital glands arethe glands in the area around the eyeball including, for example, themeibomian, lacrimal, and/or accessory lacrimal glands. In someembodiments, the pharmaceutical composition is specifically formulatedfor peri-ocular delivery. In some embodiments, the pharmaceuticallyacceptable carrier is adapted for peri-ocular transdermal deliveryby: 1) decreasing the concentration of the permeation enhancer in thecarrier relative to the concentration used in a standard ointment/creamor ophthalmic formulation; 2) using a permeation enhancer (not typicallyfound in topical steroid ointment/cream formulations) that is suitablefor transdermal delivery of the compound into the eyelid (e.g.,Tween-80); 3) formulating the pharmaceutical composition to achieveimproved spreadability on the peri-ocular surface relative to anointment base; and/or 4) formulating the pharmaceutical composition toavoid flow from the pen-ocular surface onto the corneal surface. In someembodiments, the pharmaceutical compositions are adapted for pen-oculartransdermal delivery to significantly enhance the ocular safety of thedelivered lipophilic compound by: 1) decreasing the concentration of thepermeation enhancer in the pharmaceutical composition relative to theconcentration used in a standard ointment/cream or ophthalmicformulation; 2) using a permeation enhancer (not typically found intopical steroid ointment/cream formulations) that is suitable fortransdermal delivery of the compound into the eyelid (e.g., Tween-80);3) formulating the pharmaceutical composition to achieve improvedspreadability on the pen-ocular surface relative to an ointment base; 4)formulating the pharmaceutical composition to avoid flow from theperi-ocular surface onto the corneal surface; 5) using a novel steroidsuch as the compound of Formula I (which has been specifically developedwith an ability to enable the glucocorticoid receptor to transrepressgene activation with less or little transactivation) in an effort toreduce the side effects of glucocorticoids that are thought to bemediated through transactivation; 6) using the Meibomian glands, meibum,and other fatty structures in the eyelids as a drug depot of alipophilic compound for sustained delivery to the ocular surface; and/or7) use of the Meibomian glands and meibum as a novel drug deliverysystem for a pharmaceutical formulation of a lipophilic compound appliedperi-ocularly to the outside of the upper and/or lower eyelid(s).

In some embodiments, the pharmaceutical composition further comprises atherapeutically effective amount of at least one additional steroid,antibiotic, immunomodulatory drug, integrin antagonist,anti-inflammatory agent, and/or anti-glaucoma or ocularanti-hypertension agent, in any combination. In some embodimentscomprising a lipophilic compound and further comprising at least oneadditional steroid, antibiotic, immunomodulatory drug, integrinantagonist, anti-inflammatory agent, and/or anti-glaucoma or ocularanti-hypertension agent, the lipophilic compound is different from theat least one additional steroid, antibiotic, immunomodulatory drug,integrin antagonist, anti-inflammatory agent, and/or anti-glaucoma orocular anti-hypertension agent. In some embodiments, the pharmaceuticalcomposition is specifically formulated for peri-ocular delivery inaccordance with the teachings herein.

In some embodiments, the lipophilic compound is not deliveredsystemically when the pharmaceutical composition is administered to thesubject. In some embodiments, the lipophilic compound is not deliveredby direct application into the tears and/or tear ducts of the subject.In some embodiments, the lipophilic compound is not delivered by directapplication to an ocular surface of the subject (e.g., the cornea,conjunctiva). In some embodiments, the pharmaceutical composition is nota liquid topical ocular suspension, emulsion, or suspension (i.e., eyedrops). In some embodiments, the lipophilic compound is a steroid. Insome embodiments, the lipophilic compound is an antibiotic. In someembodiments, the lipophilic compound is an immunomodulatory drug. Insome embodiments, the lipophilic compound is an integrin antagonist. Insome embodiments, the lipophilic compound is an anti-inflammatory agent.In some embodiments, the lipophilic compound is an anti-glaucoma orocular anti-hypertension agent.

Steroids

In some aspects, the present disclosure relates to a pharmaceuticalcomposition comprising a steroid as the lipophilic compound.Accordingly, in some embodiments, the pharmaceutical compositioncomprises a therapeutically effective amount of a steroid, and apharmaceutically acceptable carrier adapted for pen-ocular transdermaldelivery of the steroid to one or more pen-orbital (e.g., oil-secretingpen-orbital) glands of a subject, wherein the pharmaceutical compositionis specifically formulated for pen-ocular delivery. Any suitable steroidknown in the art may be used in a pharmaceutical composition of thepresent disclosure, including, for example, the compound of Formula I,fluocinolone, medrysone, difluprednate, fluticasone, fluorometholone,loteprednol, dexamethasone, prednisolone, triamcinolone acetonide,rimexolone, cortisol, cortisone, hydrocortisone, and testosterone, orany ester derivatives thereof. In some embodiments, the steroid is aglucocorticoid. In some embodiments, the steroid is the compound ofFormula I, difluprednate, loteprednol, dexamethasone, prednisolone,triamcinolone acetonide, or any ester derivative thereof. In someembodiments, the steroid is the compound of Formula I. As used herein,“the compound of Formula I” refers to the compound 6a,9a-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tetramethycyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carboxylicacid cyanomethyl ester. See e.g., U.S. Pat. No. 7,291,609, including formethods of making the same. A structure of the compound of Formula I isshown below:

In some embodiments, the pharmaceutical composition comprises thesteroid at a concentration between 0.001% and 10% weight per weight(w/w). For example, the pharmaceutical composition may comprise thesteroid at a concentration from about 0.001% to about 10%, from about0.001% to about 9%, from about 0.001% to about 8%, from about 0.001% toabout 7%, from about 0.001% to about 6%, from about 0.001% to about 5%,from about 0.001% to about 4%, from about 0.001% to about 3%, from about0.001% to about 2%, from about 0.001% to about 1%, from about 0.001% toabout 0.5%, from about 0.001% to about 0.1%, from about 0.001% to about0.05%, from about 0.001% to about 0.01%, from about 0.001% to about0.005%, from about 0.01% to about 10%, from about 0.01% to about 9%,from about 0.01% to about 8%, from about 0.01% to about 7%, from about0.01% to about 6%, from about 0.01% to about 5%, from about 0.01% toabout 4%, from about 0.01% to about 3%, from about 0.01% to about 2%,from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about0.01% to about 0.1%, from about 0.01% to about 0.05%, from about 0.05%to about 10%, from about 0.05% to about 9%, from about 0.05% to about8%, from about 0.05% to about 7%, from about 0.05% to about 6%, fromabout 0.05% to about 5%, from about 0.05% to about 4%, from about 0.05%to about 3%, from about 0.05% to about 2%, from about 0.05% to about 1%,from about 0.05% to about 0.5%, from about 0.05% to about 0.1%, fromabout 0.1% to about 10%, from about 0.1% to about 9%, from about 0.1% toabout 8%, from about 0.1% to about 7%, from about 0.1% to about 6%, fromabout 0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% toabout 3%, from about 0.1% to about 2%, from about 0.1% to about 1%, fromabout 0.1% to about 0.5%, from about 0.5% to about 10%, from about 0.5%to about 9%, from about 0.5% to about 8%, from about 0.5% to about 7%,from about 0.5% to about 6%, from about 0.5% to about 5%, from about0.5% to about 4%, from about 0.5% to about 3%, from about 0.5% to about2%, from about 0.5% to about 1%, from about 1% to about 10%, from about1% to about 9%, from about 1% to about 8%, from about 1% to about 7%,from about 1% to about 6%, from about 1% to about 5%, from about 1% toabout 4%, from about 1% to about 3%, from about 1% to about 2%, fromabout 2% to about 10%, from about 2% to about 9%, from about 2% to about8%, from about 2% to about 7%, from about 2% to about 6%, from about 2%to about 5%, from about 2% to about 4%, from about 2% to about 3%, fromabout 3% to about 10%, from about 3% to about 9%, from about 3% to about8%, from about 3% to about 7%, from about 3% to about 6%, from about 3%to about 5%, from about 3% to about 4%, from about 4% to about 10%, fromabout 4% to about 9%, from about 4% to about 8%, from about 4% to about7%, from about 4% to about 6%, from about 4% to about 5%, from about 5%to about 10%, from about 5% to about 9%, from about 5% to about 8%, fromabout 5% to about 7%, from about 5% to about 6%, from about 6% to about10%, from about 6% to about 9%, from about 6% to about 8%, from about 6%to about 7%, from about 7% to about 10%, from about 7% to about 9%, fromabout 7% to about 8%, from about 8% to about 10%, from about 8% to about9%, or from about 9% to about 10% w/w. In some embodiments, thepharmaceutical composition comprises the steroid from about 0.01% toabout 2% w/w. In some embodiments, the pharmaceutical compositioncomprises the steroid at any of a concentration of about 0.001%, 0.005%,0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%,1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%, 4.5%, 5%,5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w/w.

Antibiotics

In some aspects, the present disclosure relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of anantibiotic as the lipophilic compound. In some embodiments, thepharmaceutical composition comprises two or more (e.g., two or more,three or more, four or more, five or more, etc.) antibiotics.Accordingly, in some embodiments, the pharmaceutical compositioncomprises a therapeutically effective amount of an antibiotic, and apharmaceutically acceptable carrier adapted for pen-ocular transdermaldelivery of the antibiotic to one or more pen-orbital (e.g.,oil-secreting pen-orbital) glands of a subject, wherein thepharmaceutical composition is specifically formulated for pen-oculardelivery. Any suitable antibiotic known in the art may be used in thepharmaceutical compositions of the present disclosure, including, forexample, sulfonamides, macrolides, chloramphenicol, aminoglycosides,fluoroquinolones, vancomycin, tetracyclines, and any combinationsthereof. Examples of such antibiotics include, without limitation,azithromycin, erythromycin, gentamicin, natamycin, neomycin, tobramycin,vancomycin, bacitracin, besifloxacin, ciprofloxacin, gatifloxacin,levofloxacin, moxifloxacin, oxifloxacin, chloramphenicol, doxycycline,tetracyclin, gramicidin, mupirocin, polymyxin B, sulfacetamide.

In some embodiments, the pharmaceutical composition comprises theantibiotic at a concentration between 0.0001% and 10% weight per weight(w/w). For example, the pharmaceutical composition may comprise theantibiotic at a concentration from about from about 0.0001% to about10%, from about 0.0001% to about 9%, from about 0.0001% to about 8%,from about 0.0001% to about 7%, from about 0.0001% to about 6%, fromabout 0.0001% to about 5%, from about 0.0001% to about 4%, from about0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001%to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% toabout 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% toabout 0.01%, from about 0.0001% to about 0.005%, about 0.0001% to about0.001%, about 0.0001% to about 0.0005%, about 0.0005% to about 10%, fromabout 0.0005% to about 9%, from about 0.0005% to about 8%, from about0.0005% to about 7%, from about 0.0005% to about 6%, from about 0.0005%to about 5%, from about 0.0005% to about 4%, from about 0.0005% to about3%, from about 0.0005% to about 2%, from about 0.0005% to about 1%, fromabout 0.0005% to about 0.5%, from about 0.0005% to about 0.1%, fromabout 0.0005% to about 0.05%, from about 0.0005% to about 0.01%, fromabout 0.0005% to about 0.005%, about 0.0005% to about 0.001%, about0.001% to about 10%, from about 0.001% to about 9%, from about 0.001% toabout 8%, from about 0.001% to about 7%, from about 0.001% to about 6%,from about 0.001% to about 5%, from about 0.001% to about 4%, from about0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% toabout 1%, from about 0.001% to about 0.5%, from about 0.001% to about0.1%, from about 0.001% to about 0.05%, from about 0.001% to about0.01%, from about 0.001% to about 0.005%, from about 0.01% to about 10%,from about 0.01% to about 9%, from about 0.01% to about 8%, from about0.01% to about 7%, from about 0.01% to about 6%, from about 0.01% toabout 5%, from about 0.01% to about 4%, from about 0.01% to about 3%,from about 0.01% to about 2%, from about 0.01% to about 1%, from about0.01% to about 0.5%, from about 0.01% to about 0.1%, from about 0.01% toabout 0.05%, from about 0.05% to about 10%, from about 0.05% to about9%, from about 0.05% to about 8%, from about 0.05% to about 7%, fromabout 0.05% to about 6%, from about 0.05% to about 5%, from about 0.05%to about 4%, from about 0.05% to about 3%, from about 0.05% to about 2%,from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about0.05% to about 0.1%, from about 0.1% to about 10%, from about 0.1% toabout 9%, from about 0.1% to about 8%, from about 0.1% to about 7%, fromabout 0.1% to about 6%, from about 0.1% to about 5%, from about 0.1% toabout 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, fromabout 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.5%to about 10%, from about 0.5% to about 9%, from about 0.5% to about 8%,from about 0.5% to about 7%, from about 0.5% to about 6%, from about0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about1% to about 10%, from about 1% to about 9%, from about 1% to about 8%,from about 1% to about 7%, from about 1% to about 6%, from about 1% toabout 5%, from about 1% to about 4%, from about 1% to about 3%, fromabout 1% to about 2%, from about 2% to about 10%, from about 2% to about9%, from about 2% to about 8%, from about 2% to about 7%, from about 2%to about 6%, from about 2% to about 5%, from about 2% to about 4%, fromabout 2% to about 3%, from about 3% to about 10%, from about 3% to about9%, from about 3% to about 8%, from about 3% to about 7%, from about 3%to about 6%, from about 3% to about 5%, from about 3% to about 4%, fromabout 4% to about 10%, from about 4% to about 9%, from about 4% to about8%, from about 4% to about 7%, from about 4% to about 6%, from about 4%to about 5%, from about 5% to about 10%, from about 5% to about 9%, fromabout 5% to about 8%, from about 5% to about 7%, from about 5% to about6%, from about 6% to about 10%, from about 6% to about 9%, from about 6%to about 8%, from about 6% to about 7%, from about 7% to about 10%, fromabout 7% to about 9%, from about 7% to about 8%, from about 8% to about10%, from about 8% to about 9%, or from about 9% to about 10% w/w. Insome embodiments, the pharmaceutical composition comprises theantibiotic at a concentration between 0.0001% and 5% weight per weight(w/w). In some embodiments, the pharmaceutical composition comprises theantibiotic at any of a concentration of about 0.0001%, 0.0005%, 0.001%,0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%,0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%,0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%,0.95%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%,4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w/w.

Immunomodulatory Drugs

In some aspects, the present disclosure relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of animmunomodulatory drug as the lipophilic compound. In some embodiments,the pharmaceutical composition comprises two or more (e.g., two or more,three or more, four or more, five or more, etc.) immunomodulatory drugs.Accordingly, in some embodiments, the pharmaceutical compositioncomprises a therapeutically effective amount of an immunomodulatorydrug, and a pharmaceutically acceptable carrier adapted for pen-oculartransdermal delivery of the immunomodulatory drug to one or morepen-orbital (e.g., oil-secreting peri-orbital) glands of a subject,wherein the pharmaceutical composition is specifically formulated forperi-ocular delivery. Any suitable immunomodulatory drug known in theart may be used in the pharmaceutical compositions of the presentdisclosure, including, for example, calcineurin inhibitors, thalidomideanalogues, and any combinations thereof. Examples of suchimmunomodulatory drugs include, without limitation, cyclosporine A,voclosporine, tacrolimus, pimecrolimus, thalidomide, lenalidomide, andpomalidomide. In some embodiments, the immunomodulatory drug iscyclosporine A.

In some embodiments, the pharmaceutical composition comprises theimmunomodulatory drug at a concentration between 0.0001% and 5% weightper weight (w/w). For example, the pharmaceutical composition maycomprise the immunomodulatory drug at a concentration from about 0.0001%to about 5%, from about 0.0001% to about 4%, from about 0.0001% to about3%, from about 0.0001% to about 2%, from about 0.0001% to about 1%, fromabout 0.0001% to about 0.5%, from about 0.0001% to about 0.1%, fromabout 0.0001% to about 0.05%, from about 0.0001% to about 0.01%, fromabout 0.0001% to about 0.005%, from about 0.0001% to about 0.001%, fromabout 0.0001% to about 0.0005%, from about 0.0005% to about 5%, fromabout 0.0005% to about 4%, from about 0.0005% to about 3%, from about0.0005% to about 2%, from about 0.0005% to about 1%, from about 0.0005%to about 0.5%, from about 0.0005% to about 0.1%, from about 0.0005% toabout 0.05%, from about 0.0005% to about 0.01%, from about 0.0005% toabout 0.005%, from about 0.0005% to about 0.001%, from about 0.001% toabout 5%, from about 0.001% to about 4%, from about 0.001% to about 3%,from about 0.001% to about 2%, from about 0.001% to about 1%, from about0.001% to about 0.5%, from about 0.001% to about 0.1%, from about 0.001%to about 0.05%, from about 0.001% to about 0.01%, from about 0.001% toabout 0.005%, from about 0.005% to about 5%, from about 0.005% to about4%, from about 0.005% to about 3%, from about 0.005% to about 2%, fromabout 0.005% to about 1%, from about 0.005% to about 0.5%, from about0.005% to about 0.1%, from about 0.005% to about 0.05%, from about0.005% to about 0.01%, from about 0.01% to about 5%, from about 0.01% toabout 4%, from about 0.01% to about 3%, from about 0.01% to about 2%,from about 0.01% to about 1%, from about 0.01% to about 0.5%, from about0.01% to about 0.1%, from about 0.01% to about 0.05%, from about 0.05%to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%,from about 0.05% to about 2%, from about 0.05% to about 1%, from about0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% toabout 5%, from about 0.1% to about 4%, from about 0.1% to about 3%, fromabout 0.1% to about 2%, from about 0.1% to about 1%, from about 0.1% toabout 0.5%, from about 0.5% to about 5%, from about 0.5% to about 4%,from about 0.5% to about 3%, from about 0.5% to about 2%, from about0.5% to about 1%, from about 1% to about 5%, from about 1% to about 4%,from about 1% to about 3%, from about 1% to about 2%, from about 2% toabout 5%, from about 2% to about 4%, from about 2% to about 3%, fromabout 3% to about 5%, from about 3% to about 4%, or from about 4% toabout 5% w/w. In some embodiments, the pharmaceutical compositioncomprises the immunomodulatory drug at any of a concentration of about0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%,0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%,0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%,0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 2%, 3%, 4%, or 5% w/w.

Integrin Antagonists

In some aspects, the present disclosure relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of an integrinantagonist as the lipophilic compound. In some embodiments, thepharmaceutical composition comprises two or more (e.g., two or more,three or more, four or more, five or more, etc.) integrin antagonists.Accordingly, in some embodiments, the pharmaceutical compositioncomprises a therapeutically effective amount of an integrin antagonist,and a pharmaceutically acceptable carrier adapted for peri-oculartransdermal delivery of the integrin antagonist to one or morepen-orbital (e.g., oil-secreting pen-orbital) glands of a subject,wherein the pharmaceutical composition is specifically formulated forpen-ocular delivery. Any suitable integrin antagonist known in the artmay be used in the pharmaceutical compositions of the presentdisclosure, including, for example, lifitegrast, GW559090, esterderivatives thereof, and any combinations thereof. In some embodiments,the pharmaceutical composition comprises GW559090 (See Krauss et al.Invest. Ophthalmol. Vis. Sci. 2015;56(10):5888-95).

In some embodiments, the pharmaceutical composition comprises theintegrin antagonist at a concentration between 0.0001% and 10% weightper weight (w/w). For example, the pharmaceutical composition maycomprise the integrin antagonist at a concentration from about 0.0001%to about 10%, from about 0.0001% to about 9%, from about 0.0001% toabout 8%, from about 0.0001% to about 7%, from about 0.0001% to about6%, from about 0.0001% to about 5%, from about 0.0001% to about 4%, fromabout 0.0001% to about 3%, from about 0.0001% to about 2%, from about0.0001% to about 1%, from about 0.0001% to about 0.5%, from about0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about0.0001% to about 0.01%, from about 0.0001% to about 0.005%, about0.0001% to about 0.001%, about 0.0001% to about 0.0005%, about 0.0005%to about 10%, from about 0.0005% to about 9%, from about 0.0005% toabout 8%, from about 0.0005% to about 7%, from about 0.0005% to about6%, from about 0.0005% to about 5%, from about 0.0005% to about 4%, fromabout 0.0005% to about 3%, from about 0.0005% to about 2%, from about0.0005% to about 1%, from about 0.0005% to about 0.5%, from about0.0005% to about 0.1%, from about 0.0005% to about 0.05%, from about0.0005% to about 0.01%, from about 0.0005% to about 0.005%, about0.0005% to about 0.001%, about 0.001% to about 10%, from about 0.001% toabout 9%, from about 0.001% to about 8%, from about 0.001% to about 7%,from about 0.001% to about 6%, from about 0.001% to about 5%, from about0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% toabout 2%, from about 0.001% to about 1%, from about 0.001% to about0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%,from about 0.001% to about 0.01%, from about 0.001% to about 0.005%,from about 0.01% to about 10%, from about 0.01% to about 9%, from about0.01% to about 8%, from about 0.01% to about 7%, from about 0.01% toabout 6%, from about 0.01% to about 5%, from about 0.01% to about 4%,from about 0.01% to about 3%, from about 0.01% to about 2%, from about0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% toabout 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about10%, from about 0.05% to about 9%, from about 0.05% to about 8%, fromabout 0.05% to about 7%, from about 0.05% to about 6%, from about 0.05%to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%,from about 0.05% to about 2%, from about 0.05% to about 1%, from about0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% toabout 10%, from about 0.1% to about 9%, from about 0.1% to about 8%,from about 0.1% to about 7%, from about 0.1% to about 6%, from about0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about0.1% to about 0.5%, from about 0.5% to about 10%, from about 0.5% toabout 9%, from about 0.5% to about 8%, from about 0.5% to about 7%, fromabout 0.5% to about 6%, from about 0.5% to about 5%, from about 0.5% toabout 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, fromabout 0.5% to about 1%, from about 1% to about 10%, from about 1% toabout 9%, from about 1% to about 8%, from about 1% to about 7%, fromabout 1% to about 6%, from about 1% to about 5%, from about 1% to about4%, from about 1% to about 3%, from about 1% to about 2%, from about 2%to about 10%, from about 2% to about 9%, from about 2% to about 8%, fromabout 2% to about 7%, from about 2% to about 6%, from about 2% to about5%, from about 2% to about 4%, from about 2% to about 3%, from about 3%to about 10%, from about 3% to about 9%, from about 3% to about 8%, fromabout 3% to about 7%, from about 3% to about 6%, from about 3% to about5%, from about 3% to about 4%, from about 4% to about 10%, from about 4%to about 9%, from about 4% to about 8%, from about 4% to about 7%, fromabout 4% to about 6%, from about 4% to about 5%, from about 5% to about10%, from about 5% to about 9%, from about 5% to about 8%, from about 5%to about 7%, from about 5% to about 6%, from about 6% to about 10%, fromabout 6% to about 9%, from about 6% to about 8%, from about 6% to about7%, from about 7% to about 10%, from about 7% to about 9%, from about 7%to about 8%, from about 8% to about 10%, from about 8% to about 9%, orfrom about 9% to about 10% w/w. In some embodiments, the pharmaceuticalcomposition comprises the integrin antagonist at any of a concentrationof about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%,0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%,0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%,0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.25%, 1.5%, 1.75%,2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%,7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w/w.

Anti-Inflammatory Agents

In some aspects, the present disclosure relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of ananti-inflammatory agent as the lipophilic compound. In some embodiments,the pharmaceutical composition comprises two or more (e.g., two or more,three or more, four or more, five or more, etc.) anti-inflammatoryagents. Accordingly, in some embodiments, the pharmaceutical compositioncomprises a therapeutically effective amount of an anti-inflammatoryagent, and a pharmaceutically acceptable carrier adapted for pen-oculartransdermal delivery of the anti-inflammatory agent to one or morepen-orbital (e.g., oil-secreting peri-orbital) glands of a subject,wherein the pharmaceutical composition is specifically formulated forperi-ocular delivery. Any suitable anti-inflammatory agent known in theart may be used in the pharmaceutical compositions of the presentdisclosure, including, for example, omega 3 fatty acids, non-steroidalanti-inflammatory drugs (NSAIDS), and any combinations thereof. Examplesof suitable omega 3 fatty acids may include, without limitation,eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenicacid (ALA), and any combinations thereof. Examples of suitable NSAIDSmay include, without limitation, bromfenac, diclofenac, indomethacin,flurbiprofen, ketorolac, nepafenac, and any combinations thereof.

In some embodiments, the pharmaceutical composition comprises theanti-inflammatory agent at a concentration between 0.0001% and 5% weightper weight (w/w). For example, the pharmaceutical composition maycomprise the anti-inflammatory agent at a concentration from about0.0001% to about 5%, from about 0.0001% to about 4%, from about 0.0001%to about 3%, from about 0.0001% to about 2%, from about 0.0001% to about1%, from about 0.0001% to about 0.5%, from about 0.0001% to about 0.1%,from about 0.0001% to about 0.05%, from about 0.0001% to about 0.01%,from about 0.0001% to about 0.005%, from about 0.0001% to about 0.001%,from about 0.0001% to about 0.0005%, from about 0.0005% to about 5%,from about 0.0005% to about 4%, from about 0.0005% to about 3%, fromabout 0.0005% to about 2%, from about 0.0005% to about 1%, from about0.0005% to about 0.5%, from about 0.0005% to about 0.1%, from about0.0005% to about 0.05%, from about 0.0005% to about 0.01%, from about0.0005% to about 0.005%, from about 0.0005% to about 0.001%, from about0.001% to about 5%, from about 0.001% to about 4%, from about 0.001% toabout 3%, from about 0.001% to about 2%, from about 0.001% to about 1%,from about 0.001% to about 0.5%, from about 0.001% to about 0.1%, fromabout 0.001% to about 0.05%, from about 0.001% to about 0.01%, fromabout 0.001% to about 0.005%, from about 0.005% to about 5%, from about0.005% to about 4%, from about 0.005% to about 3%, from about 0.005% toabout 2%, from about 0.005% to about 1%, from about 0.005% to about0.5%, from about 0.005% to about 0.1%, from about 0.005% to about 0.05%,from about 0.005% to about 0.01%, from about 0.01% to about 5%, fromabout 0.01% to about 4%, from about 0.01% to about 3%, from about 0.01%to about 2%, from about 0.01% to about 1%, from about 0.01% to about0.5%, from about 0.01% to about 0.1%, from about 0.01% to about 0.05%,from about 0.05% to about 5%, from about 0.05% to about 4%, from about0.05% to about 3%, from about 0.05% to about 2%, from about 0.05% toabout 1%, from about 0.05% to about 0.5%, from about 0.05% to about0.1%, from about 0.1% to about 5%, from about 0.1% to about 4%, fromabout 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% toabout 1%, from about 0.1% to about 0.5%, from about 0.5% to about 5%,from about 0.5% to about 4%, from about 0.5% to about 3%, from about0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about5%, from about 1% to about 4%, from about 1% to about 3%, from about 1%to about 2%, from about 2% to about 5%, from about 2% to about 4%, fromabout 2% to about 3%, from about 3% to about 5%, from about 3% to about4%, or from about 4% to about 5% w/w. In some embodiments, thepharmaceutical composition comprises the anti-inflammatory agent at anyof a concentration of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%,0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%,0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%,0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 2%,3%, 4%, or 5% w/w.

Anti-Glaucoma Drugs or Ocular Anti-Hypertension Agents

In some aspects, the present disclosure relates to a pharmaceuticalcomposition comprising a therapeutically effective amount of ananti-glaucoma drug or ocular anti-hypertension agent as the lipophiliccompound. In some embodiments, the pharmaceutical composition comprisestwo or more (e.g., two or more, three or more, four or more, five ormore, etc.) anti-glaucoma drugs or ocular anti-hypertension agents.Accordingly, in some embodiments, the pharmaceutical compositioncomprises a therapeutically effective amount of an anti-glaucoma drug orocular anti-hypertension agent, and a pharmaceutically acceptablecarrier adapted for peri-ocular transdermal delivery of theanti-glaucoma drug or ocular anti-hypertension agents to one or moreperi-orbital (e.g., oil-secreting peri-orbital) glands of a subject,wherein the pharmaceutical composition is specifically formulated forperi-ocular delivery. Any suitable anti-glaucoma drug or ocularanti-hypertension agent known in the art may be used in thepharmaceutical compositions of the present disclosure, including, forexample, prostaglandin analogs, beta blockers, alpha-2 agonists,carbonic anhydrase inhibitors, Rho kinase inhibitors, and anycombinations thereof. Examples of suitable prostaglandin analogs mayinclude, without limitiation, bimatoprost, latanoprost, travoprost,tafluprost, latanoprostene-bunod, and any combinations thereof. Examplesof suitable beta blockers may include, without limitiation, timolol,betaxolol, levobunolol, metipranolol, and any combinations thereof.Examples of suitable alpha-2 agonists may include brimonidine,clonidine, apraclonidine, and any combinations thereof. Examples ofsuitable carbonic anhydrase inhibitors may include, without limitiation,dorzolamide, brinzolamide, acetazolamide, methazolamide, and anycombinations thereof. Examples of suitable Rho kinase inhibitors mayinclude, without limitiation, netarsudil, and any combinations thereof.

In some embodiments, the pharmaceutical composition comprises theanti-glaucoma drug or ocular anti-hypertension agent at a concentrationbetween 0.0001% and 10% weight per weight (w/w). For example, thepharmaceutical composition may comprise the anti-glaucoma drug or ocularanti-hypertension agent at a concentration from about 0.0001% to about10%, from about 0.0001% to about 9%, from about 0.0001% to about 8%,from about 0.0001% to about 7%, from about 0.0001% to about 6%, fromabout 0.0001% to about 5%, from about 0.0001% to about 4%, from about0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001%to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% toabout 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% toabout 0.01%, from about 0.0001% to about 0.005%, about 0.0001% to about0.001%, about 0.0001% to about 0.0005%, about 0.0005% to about 10%, fromabout 0.0005% to about 9%, from about 0.0005% to about 8%, from about0.0005% to about 7%, from about 0.0005% to about 6%, from about 0.0005%to about 5%, from about 0.0005% to about 4%, from about 0.0005% to about3%, from about 0.0005% to about 2%, from about 0.0005% to about 1%, fromabout 0.0005% to about 0.5%, from about 0.0005% to about 0.1%, fromabout 0.0005% to about 0.05%, from about 0.0005% to about 0.01%, fromabout 0.0005% to about 0.005%, about 0.0005% to about 0.001%, about0.001% to about 10%, from about 0.001% to about 9%, from about 0.001% toabout 8%, from about 0.001% to about 7%, from about 0.001% to about 6%,from about 0.001% to about 5%, from about 0.001% to about 4%, from about0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% toabout 1%, from about 0.001% to about 0.5%, from about 0.001% to about0.1%, from about 0.001% to about 0.05%, from about 0.001% to about0.01%, from about 0.001% to about 0.005%, from about 0.01% to about 10%,from about 0.01% to about 9%, from about 0.01% to about 8%, from about0.01% to about 7%, from about 0.01% to about 6%, from about 0.01% toabout 5%, from about 0.01% to about 4%, from about 0.01% to about 3%,from about 0.01% to about 2%, from about 0.01% to about 1%, from about0.01% to about 0.5%, from about 0.01% to about 0.1%, from about 0.01% toabout 0.05%, from about 0.05% to about 10%, from about 0.05% to about9%, from about 0.05% to about 8%, from about 0.05% to about 7%, fromabout 0.05% to about 6%, from about 0.05% to about 5%, from about 0.05%to about 4%, from about 0.05% to about 3%, from about 0.05% to about 2%,from about 0.05% to about 1%, from about 0.05% to about 0.5%, from about0.05% to about 0.1%, from about 0.1% to about 10%, from about 0.1% toabout 9%, from about 0.1% to about 8%, from about 0.1% to about 7%, fromabout 0.1% to about 6%, from about 0.1% to about 5%, from about 0.1% toabout 4%, from about 0.1% to about 3%, from about 0.1% to about 2%, fromabout 0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.5%to about 10%, from about 0.5% to about 9%, from about 0.5% to about 8%,from about 0.5% to about 7%, from about 0.5% to about 6%, from about0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about1% to about 10%, from about 1% to about 9%, from about 1% to about 8%,from about 1% to about 7%, from about 1% to about 6%, from about 1% toabout 5%, from about 1% to about 4%, from about 1% to about 3%, fromabout 1% to about 2%, from about 2% to about 10%, from about 2% to about9%, from about 2% to about 8%, from about 2% to about 7%, from about 2%to about 6%, from about 2% to about 5%, from about 2% to about 4%, fromabout 2% to about 3%, from about 3% to about 10%, from about 3% to about9%, from about 3% to about 8%, from about 3% to about 7%, from about 3%to about 6%, from about 3% to about 5%, from about 3% to about 4%, fromabout 4% to about 10%, from about 4% to about 9%, from about 4% to about8%, from about 4% to about 7%, from about 4% to about 6%, from about 4%to about 5%, from about 5% to about 10%, from about 5% to about 9%, fromabout 5% to about 8%, from about 5% to about 7%, from about 5% to about6%, from about 6% to about 10%, from about 6% to about 9%, from about 6%to about 8%, from about 6% to about 7%, from about 7% to about 10%, fromabout 7% to about 9%, from about 7% to about 8%, from about 8% to about10%, from about 8% to about 9%, or from about 9% to about 10% w/w. Insome embodiments, the pharmaceutical composition comprises theanti-glaucoma drug or ocular anti-hypertension agent at any of aconcentration of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%,0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%,0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%,0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.25%,1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%,6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w/w.

Pharmaceutically Acceptable Carrier

In some aspects, the present disclosure relates to a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier adapted forperi-ocular transdermal delivery of a steroid to one or moreperi-orbital glands of a subject. In some embodiments, thepharmaceutically acceptable carrier is adapted for peri-oculartransdermal delivery by: 1) decreasing the concentration of thepermeation enhancer in the carrier relative to the concentration used ina standard steroid ointment/cream formulation; 2) using a permeationenhancer (not typically found in topical steroid ointment/creamformulations) that is suitable for transdermal delivery of the steroidinto the eyelid (e.g., Tween-80); 3) formulating the pharmaceuticalcomposition to achieve improved spreadability on the peri-ocular surfacerelative to an ointment base; and/or 4) formulating the pharmaceuticalcomposition to avoid flow from the pen-ocular surface onto the cornealsurface.

In some embodiments, the pharmaceutically acceptable carrier comprisesone or more (e.g., one or more, two or more, three or more, four ormore, five or more, etc.) permeation enhancers. As used herein, a“permeation enhancer” or “penetration enhancer” may refer to a compoundor mixture of compounds that interact with one or more skin constituentsto promote drug penetration into and/or through the skin. Any suitablepermeation enhancer known in the art may be used in the pharmaceuticalcompositions described herein, including, for example, surfactants(e.g., ionic (anionic, cationic, zwitterionic) surfactants (such assodium lauryl sulfate, sodium laureate, etc.) non-ionic surfactants(such as Tween-80, other polysorbates, etc.), and any combinationsthereof), bile salts and derivatives thereof (e.g., sodium glyacolate,sodium deoxycholate, etc.), fatty acids and derivatives thereof (e.g.,oleic acid, caprylic acid, esters of fatty acids such as isopropylmyrisate, etc.), chelating agents (e.g., EDTA, citric acid, etc.),sulphoxides (e.g., DMSO, DMA, DMF, etc.), polyols (e.g., diethyleneglycol monoethyl ether, PG, polyethylene glycols (PEGs), glycerol,polyglycols, etc.), alcohols (e.g., alkanols, alkenols, glycols, etc.),hydrocarbons (e.g., alkanes, alkenes, halogenated alkanes, squalene,squalene, mineral oil, etc.), amines, amides (e.g., cyclic amides,acyclic amides, azones, pyrrolidones, urea and derivatives thereof,etc.), others (e.g., terpenes and terpenoids, essential oils (such aseucalyptus oil, peppermint oil, turpentine oil, etc.), phospholipids,cyclic oligosaccharides (such as cyclodextrins), amino acids andthioacyl derivatives of amino acids, alkyl amino esters andoxazolidinones, enzymes, ketones (such as macrocyclic ketones), etc.),hyaluronic acid, benzalkonium chloride, and any combinations thereof.

In some embodiments, the pharmaceutically acceptable carrier is adaptedfor peri-ocular transdermal delivery by comprising a decreasedconcentration of the permeation enhancer relative to the concentrationof permeation enhancer used in a typical steroid ointment/creamformulation. In some embodiments, the pharmaceutically acceptablecarrier comprises about 95%, about 90%, about 85%, about 80%, about 75%,about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about40%, about 35%, about 30%, about 35%, about 20%, about 15%, about 10%,about 5%, about 1%, about 0.1%, or about 0.01% of the concentration ofthe permeation enhancer as compared to the concentration of thepermeation enhanced used in a typical steroid ointment/cream formulationfor dermal application. In some embodiments, the pharmaceuticallyacceptable carrier comprises about 1-fold, about 2-fold about 3-foldabout 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold,about 9-fold, about 10-fold, about 20-fold, about 30-fold, about40-fold, about 50-fold or about 100-fold less permeation enhancer ascompared to the concentration of the permeation enhanced used in atypical steroid ointment/cream formulation for dermal application. Forexample, if a typical steroid ointment comprises a given permeationenhancer (e.g., hydroxypropyl methylcellulose) at 3% w/w, then thepharmaceutical compositions of the present disclosure may include thesame permeation enhancer at about 2.85%, about 2.7%, about 2.55%, about2.4%, about 2.25%, about 2.1%, about 1.95%, aboutl.8%, about 1.65%,about 1.5%, about 1.35%, about 1.2% about 1.05%, about 0.9%, about0.75%, about 0.6%, about 0.45%, about 0.3%, about 0.03%, or about 0.003%w/w.

In some embodiments, the pharmaceutically acceptable carrier is adaptedfor peri-ocular transdermal delivery by comprising a permeation enhancerthat is suitable for transdermal delivery of a steroid into the eyelid(e.g., but not completely through to the topical surface) of a subject.In some embodiments, the permeation enhancer that is suitable fortransdermal delivery into the eyelid is a permeation enhancerspecifically suitable for transdermal delivery adjacent to the eyeand/or not typically found in topical steroid ointment/creamformulations (for use on other areas of the body of a subject like thehands or feet). Examples of suitable permeation enhancers for deliveryinto the eyelid of the subject may include, without limitation,Tween-80, polyethylene glycols (PEGS), diethylene glycol monoethylether, essential oils, hyaluronic acid, benzalkonium chloride (BAK),and/or any combinations thereof.

In some embodiments, the pharmaceutically acceptable carrier is adaptedfor peri-ocular transdermal delivery by formulating the carrier to 1)achieve improved spreadability on the pen-ocular surface relative to anointment base; and/or 2) avoid flow from the peri-ocular surface ontothe corneal surface. After application of a typical steroid ointment orcream to the skin, body heat absorbed by the cream or ointment leads toa decrease in viscosity and/or yield stress, causing a decrease incohesiveness on contact surfaces, such as the pen-ocular skin.Decreasing cohesiveness after heat absorption is problematic for anointment or cream being applied to the eyelids, as decreasedcohesiveness can lead to the cream or ointment spreading/flowing ontothe ocular surface. In some embodiments, the pharmaceutically acceptablecarrier comprises characteristics and rheological features of improvedspreadability, resulting in easier administration and spreading onto theeyelid surface, and absence of flow at the body temperature of a subject(e.g., 31° C., 33° C., 35° C., 37° C., etc.), particularly after beingapplied to the skin of a subject. In some embodiments, pharmaceuticalcompositions of the present disclosure are formulated such that thecohesiveness of the formulation does not significantly change afterapplication to the skin (e.g., eyelids) of a subject. Examples ofsuitable additives that convey a suitable cohesiveness of theformulation may include, for example, additives that increase viscosityof the formulation such as waxes, paraffins, and elastomers. In someembodiments, the viscosity of the pharmaceutically acceptable carrierdoes not significantly change when heated from room temperature (e.g.,25° C.) to a temperature closer to the body temperature of a subject(e.g., 31° C., 33° C., 35° C., 37° C., etc.). In some embodiments, theviscosity of the pharmaceutically acceptable carrier does not change bymore than about 10%, more than about 9%, more than about 8%, more thanabout 7%, more than about 6%, more than about 5%, more than about 4%,more than about 3%, more than about 2%, more than about 1%, more thanabout 0.5%, more than about 0.1%, or more than about 0.01% when heatedfrom room temperature (e.g., approximately 20° C., 21° C., 22° C., 23° ,C24° C., or 25° C.) to a temperature (e.g., approximately 30° C., 31°C., 32° C., 33° C., 34° C., 35° C., 36° C., or 37° C.) closer to thebody temperature of the subject.

In some embodiments, the pharmaceutically acceptable carrier is anointment, cream, lotion, gel, emulsion, suspension, oil, foam,transdermal patch, spray, or any combination thereof. In someembodiments, the pharmaceutically acceptable carrier is an ointment. Insome embodiments, the pharmaceutically acceptable carrier is a cream. Insome embodiments, the pharmaceutically acceptable carrier comprises oneor more of buffers such as phosphate, citrate, and other organic acids;antioxidants including ascorbic acid and methionine; preservatives (suchas octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride; benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides, and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; polyols such as glycerol (e.g.,formulations including 10% glycerol) or propylene glycol; salt-formingcounter-ions such as sodium; metal complexes (e.g. Zn-proteincomplexes); and/or non-ionic surfactants such as polyethylene glycol(PEG). A thorough discussion of pharmaceutically acceptable carriers isavailable in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., N.J.1991).

In some embodiments, the pharmaceutically acceptable carrier furthercomprises one or more additional components. Examples of additionalcomponents may include, but are not limited to, binding agents (e.g.,pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose, etc.); fillers (e.g., lactose and other sugars,microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethylcellulose, polyacrylates or calcium hydrogen phosphate, etc.);lubricants (e.g., magnesium stearate, talc, silica, colloidal silicondioxide, stearic acid, metallic stearates, hydrogenated vegetable oils,corn starch, polyethylene glycols, sodium benzoate, sodium acetate,etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.);wetting agents (e.g., sodium lauryl sulphate, etc.); salt solutions;alcohols; polyethylene glycols; gelatin; lactose; amylase; magnesiumstearate; talc; silicic acid; viscous paraffin; hydroxymethylcellulose;polyvinylpyrrolidone; perfuming agents; colorants; moisturizers;sunscreens; and the like.

In some embodiments, the pharmaceutically acceptable carrier is anointment comprising a water-miscible ointment base. In some embodiments,the pharmaceutically acceptable carrier is an ointment comprising aparaffinic ointment base. In some embodiments, the ointment comprisesone or more (e.g., one or more, two or more, three or more, four ormore, five or more, six or more, seven or more, eight of more, or allnine) of white soft paraffin, mineral oil, propylene glycol, STcyclomethicone-SNF, labrasol, propylene carbonate, steareth 2, STemulsifier 10, and ST elastomer-10. In some embodiments, the ointmentcomprises white soft paraffin, mineral oil, propylene glycol, STcyclomethicone-SNF, labrasol, propylene carbonate, steareth 2, STemulsifier 10, and ST elastomer-10. In some embodiments, the ointmentcomprises about 61.5% w/w white soft paraffin, about 8% w/w mineral oil,about 8% w/w propylene glycol, about 5% w/w of ST cyclomethicone-SNF,about 5% w/w of labrasol, about 5% w/w of propylene carbonate, about2.5% w/w of steareth 2, about 2.5% w/w of St. emulsifier 10, and about2.5% w/w of St. elastomer-10.

In some embodiments, the pharmaceutically acceptable carrier is a creamcomprising an oil-in-water base. In some embodiments, thepharmaceutically acceptable carrier is a cream comprising a water-in-oilbase. In some embodiments, the cream comprises one or more (e.g., one ormore, two or more, three or more, four or more, five or more, six ormore, seven or more, eight or more, nine or more, 10 or more, 11 ormore, 12 or more, or all 13) of white soft paraffin/petrolatum, mineraloil, propylene glycol, cyclomethicone, ST-cyclomethicone-SNF, emulsifier10, ST-emulsifier, ST-elastomer-10, methylparaben, dibasic sodiumphosphate, citric acid, propylparaben, and purified water. In someembodiments, the cream comprises white soft paraffin/petrolatum, mineraloil, propylene glycol, ST-cyclomethicone-SNF, ST-emulsifier,ST-elastomer-10, methylparaben, dibasic sodium phosphate, citric acid,propylparaben, and purified water. In some embodiments, the creamcomprises about 48% w/w white soft paraffin/petrolatum, about 8% w/wmineral oil, about 8% w/w propylene glycol, about 6.6% w/wST-cyclomethicone-SNF, about 3.3% w/w ST-emulsifier, about 2% w/wST-elastomer-10, about 0.08% w/w methylparaben, about 0.06% w/w dibasicsodium phosphate, about 0.05% w/w citric acid, about 0.02% w/wpropylparaben, and q.s. purified water. In some embodiments, the creamcomprises white soft paraffin/petrolatum, mineral oil, propylene glycol,cyclomethicone, emulsifier 10, ST-elastomer-10, methylparaben, sodiumphosphate dibasic anhydrous, citric acid anhydrous, propylparaben, andpurified water. In some embodiments, the cream comprises about 48% w/wwhite soft paraffin/petrolatum, about 8% w/w mineral oil, about 8% w/wpropylene glycol, about 6.6% w/w cyclomethicone, about 3.3% w/wemulsifier 10, about 2% w/w ST-elastomer-10, about 0.08% w/wmethylparaben, about 0.06% w/w sodium phosphate dibasic anhydrous, about0.046% w/w citric acid anhydrous, about 0.02% w/w propylparaben, andq.s. purified water.

In some embodiments, the cream is preservative-free comprising whitesoft paraffin/petrolatum, mineral oil, propylene glycol,ST-cyclomethicone-SNF, ST-emulsifier-10, ST-elastomer-10, dibasic sodiumphosphate, citric acid, and purified water. In some embodiments, thecream is preservative-free comprising 48% w/w white petrolatum, 8% w/wmineral oil, 8% w/w propylene glycol, 6.6% w/w ST-cyclomethicone-SNF,3.3% w/w emulsifier 10, 2% w/w ST-elastomer-10, 0.06% w/w sodiumphosphate dibasic anhydrous, 0.05% w/w citric acid anhydrous, and q.s.purified water.

Pharmaceutical compositions and formulations of the present disclosuremay be prepared by mixing the steroid with one or more pharmaceuticallyacceptable carriers. The formulations to be used for in vivoadministration are generally sterile. Sterility may be readilyaccomplished, e.g., by filtration through sterile filtration membranes,by heat exposure, and/or by gamma irradiation.

Additional Lipophilic Compounds

In some embodiments, a pharmaceutical composition of the presentdisclosure further comprises at least one (e.g., at least one, at leasttwo, at least three, at least four, or at least five, etc.) additionallipophilic compound. Thus, in some embodiments, the pharmaceuticalcomposition provided herein further comprises one or more lipophiliccompounds selected from the group consisting of steroids, antibiotics,immunomodulatory drugs, integrin antagonists, anti-inflammatory agents,anti-glaucoma agents, and ocular anti-hypertension agents, andcombinations thereof.

Steroids as Additional Lipophilic Compounds

In some embodiments, a pharmaceutical composition of the presentdisclosure further comprises at least one additional steroid. In someembodiments, the pharmaceutical composition comprises at least two(e.g., at least two, at least three, at least four, at least five, etc.)additional steroids. Any suitable steroid known in the art may be usedas the one or more additional steroids in the pharmaceuticalcomposition, including, for example, the compound of Formula I,fluocinolone, medrysone, difluprednate, fluticasone, fluorometholone,loteprednol, dexamethasone, prednisolone, triamcinolone acetonide,rimexolone, cortisol, cortisone, hydrocortisone, and testosterone, orany ester derivatives thereof. In some embodiments, the additionalsteroid is a glucocorticoid. In some embodiments, the at least oneadditional steroid is a different steroid than the first steroid in thepharmaceutical composition. For example, the first steroid may be thecompound of Formula I and the additional steroid may be triamcinoloneacetonide, dexamethasone, and/or loteprednol etabonate.

In some embodiments, the pharmaceutical composition comprises one ormore additional steroids each at a concentration between 0.001% and 10%weight per weight (w/w). For example, the pharmaceutical composition maycomprise the additional steroid at a concentration from about 0.001% toabout 10%, from about 0.001% to about 9%, from about 0.001% to about 8%,from about 0.001% to about 7%, from about 0.001% to about 6%, from about0.001% to about 5%, from about 0.001% to about 4%, from about 0.001% toabout 3%, from about 0.001% to about 2%, from about 0.001% to about 1%,from about 0.001% to about 0.5%, from about 0.001% to about 0.1%, fromabout 0.001% to about 0.05%, from about 0.001% to about 0.01%, fromabout 0.001% to about 0.005%, from about 0.01% to about 10%, from about0.01% to about 9%, from about 0.01% to about 8%, from about 0.01% toabout 7%, from about 0.01% to about 6%, from about 0.01% to about 5%,from about 0.01% to about 4%, from about 0.01% to about 3%, from about0.01% to about 2%, from about 0.01% to about 1%, from about 0.01% toabout 0.5%, from about 0.01% to about 0.1%, from about 0.01% to about0.05%, from about 0.05% to about 10%, from about 0.05% to about 9%, fromabout 0.05% to about 8%, from about 0.05% to about 7%, from about 0.05%to about 6%, from about 0.05% to about 5%, from about 0.05% to about 4%,from about 0.05% to about 3%, from about 0.05% to about 2%, from about0.05% to about 1%, from about 0.05% to about 0.5%, from about 0.05% toabout 0.1%, from about 0.1% to about 10%, from about 0.1% to about 9%,from about 0.1% to about 8%, from about 0.1% to about 7%, from about0.1% to about 6%, from about 0.1% to about 5%, from about 0.1% to about4%, from about 0.1% to about 3%, from about 0.1% to about 2%, from about0.1% to about 1%, from about 0.1% to about 0.5%, from about 0.5% toabout 10%, from about 0.5% to about 9%, from about 0.5% to about 8%,from about 0.5% to about 7%, from about 0.5% to about 6%, from about0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about1% to about 10%, from about 1% to about 9%, from about 1% to about 8%,from about 1% to about 7%, from about 1% to about 6%, from about 1% toabout 5%, from about 1% to about 4%, from about 1% to about 3%, fromabout 1% to about 2%, from about 2% to about 10%, from about 2% to about9%, from about 2% to about 8%, from about 2% to about 7%, from about 2%to about 6%, from about 2% to about 5%, from about 2% to about 4%, fromabout 2% to about 3%, from about 3% to about 10%, from about 3% to about9%, from about 3% to about 8%, from about 3% to about 7%, from about 3%to about 6%, from about 3% to about 5%, from about 3% to about 4%, fromabout 4% to about 10%, from about 4% to about 9%, from about 4% to about8%, from about 4% to about 7%, from about 4% to about 6%, from about 4%to about 5%, from about 5% to about 10%, from about 5% to about 9%, fromabout 5% to about 8%, from about 5% to about 7%, from about 5% to about6%, from about 6% to about 10%, from about 6% to about 9%, from about 6%to about 8%, from about 6% to about 7%, from about 7% to about 10%, fromabout 7% to about 9%, from about 7% to about 8%, from about 8% to about10%, from about 8% to about 9%, or from about 9% to about 10% w/w. Insome embodiments, the pharmaceutical composition comprises theadditional steroid at any of a concentration of about 0.001%, 0.005%,0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%,1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%, 4.5%, 5%,5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w/w.

In some embodiments, the pharmaceutically acceptable steroid or itsformulation has the additional advantage of not inducing thinning of theskin.

Antibiotics as Additional Lipophilic Compounds

In some embodiments, a pharmaceutical composition of the presentdisclosure further comprises a therapeutically effective amount of oneor more antibiotics. In some embodiments, the pharmaceutical compositioncomprises two or more (e.g., two or more, three or more, four or more,five or more, etc.) antibiotics. Any suitable antibiotic known in theart may be used in the pharmaceutical compositions of the presentdisclosure, including, for example, sulfonamides, macrolides,chloramphenicol, aminoglycosides, fluoroquinolones, vancomycin,tetracyclines, and any combinations thereof. Examples of suchantibiotics include, without limitation, azithromycin, erythromycin,gentamicin, natamycin, neomycin, tobramycin, vancomycin, bacitracin,besifloxacin, ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin,oxifloxacin, chloramphenicol, doxycycline, tetracyclin, gramicidin,mupirocin, polymyxin B, sulfacetamide.

In some embodiments, the pharmaceutical composition comprises the one ormore antibiotics at a concentration between 0.0001% and 10% weight perweight (w/w). For example, the pharmaceutical composition may comprisethe one or more antibiotics at a concentration from about from about0.0001% to about 10%, from about 0.0001% to about 9%, from about 0.0001%to about 8%, from about 0.0001% to about 7%, from about 0.0001% to about6%, from about 0.0001% to about 5%, from about 0.0001% to about 4%, fromabout 0.0001% to about 3%, from about 0.0001% to about 2%, from about0.0001% to about 1%, from about 0.0001% to about 0.5%, from about0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about0.0001% to about 0.01%, from about 0.0001% to about 0.005%, about0.0001% to about 0.001%, about 0.0001% to about 0.0005%, about 0.0005%to about 10%, from about 0.0005% to about 9%, from about 0.0005% toabout 8%, from about 0.0005% to about 7%, from about 0.0005% to about6%, from about 0.0005% to about 5%, from about 0.0005% to about 4%, fromabout 0.0005% to about 3%, from about 0.0005% to about 2%, from about0.0005% to about 1%, from about 0.0005% to about 0.5%, from about0.0005% to about 0.1%, from about 0.0005% to about 0.05%, from about0.0005% to about 0.01%, from about 0.0005% to about 0.005%, about0.0005% to about 0.001%, about 0.001% to about 10%, from about 0.001% toabout 9%, from about 0.001% to about 8%, from about 0.001% to about 7%,from about 0.001% to about 6%, from about 0.001% to about 5%, from about0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% toabout 2%, from about 0.001% to about 1%, from about 0.001% to about0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%,from about 0.001% to about 0.01%, from about 0.001% to about 0.005%,from about 0.01% to about 10%, from about 0.01% to about 9%, from about0.01% to about 8%, from about 0.01% to about 7%, from about 0.01% toabout 6%, from about 0.01% to about 5%, from about 0.01% to about 4%,from about 0.01% to about 3%, from about 0.01% to about 2%, from about0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% toabout 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about10%, from about 0.05% to about 9%, from about 0.05% to about 8%, fromabout 0.05% to about 7%, from about 0.05% to about 6%, from about 0.05%to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%,from about 0.05% to about 2%, from about 0.05% to about 1%, from about0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% toabout 10%, from about 0.1% to about 9%, from about 0.1% to about 8%,from about 0.1% to about 7%, from about 0.1% to about 6%, from about0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about0.1% to about 0.5%, from about 0.5% to about 10%, from about 0.5% toabout 9%, from about 0.5% to about 8%, from about 0.5% to about 7%, fromabout 0.5% to about 6%, from about 0.5% to about 5%, from about 0.5% toabout 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, fromabout 0.5% to about 1%, from about 1% to about 10%, from about 1% toabout 9%, from about 1% to about 8%, from about 1% to about 7%, fromabout 1% to about 6%, from about 1% to about 5%, from about 1% to about4%, from about 1% to about 3%, from about 1% to about 2%, from about 2%to about 10%, from about 2% to about 9%, from about 2% to about 8%, fromabout 2% to about 7%, from about 2% to about 6%, from about 2% to about5%, from about 2% to about 4%, from about 2% to about 3%, from about 3%to about 10%, from about 3% to about 9%, from about 3% to about 8%, fromabout 3% to about 7%, from about 3% to about 6%, from about 3% to about5%, from about 3% to about 4%, from about 4% to about 10%, from about 4%to about 9%, from about 4% to about 8%, from about 4% to about 7%, fromabout 4% to about 6%, from about 4% to about 5%, from about 5% to about10%, from about 5% to about 9%, from about 5% to about 8%, from about 5%to about 7%, from about 5% to about 6%, from about 6% to about 10%, fromabout 6% to about 9%, from about 6% to about 8%, from about 6% to about7%, from about 7% to about 10%, from about 7% to about 9%, from about 7%to about 8%, from about 8% to about 10%, from about 8% to about 9%, orfrom about 9% to about 10% w/w. In some embodiments, the pharmaceuticalcomposition comprises the one or more antibiotics at a concentrationbetween 0.0001% and 5% weight per weight (w/w). In some embodiments, thepharmaceutical composition comprises the one or more antibiotics at anyof a concentration of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%,0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%,0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%,0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%,1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%, 4.5%, 5%,5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w/w.

Immunomodulatory Drugs as Additional Lipophilic Compounds

In some embodiments, a pharmaceutical composition of the presentdisclosure further comprises a therapeutically effective amount of oneor more immunomodulatory drugs. In some embodiments, the pharmaceuticalcomposition comprises two or more (e.g., two or more, three or more,four or more, five or more, etc.) immunomodulatory drugs. Any suitableimmunomodulatory drug known in the art may be used in the pharmaceuticalcompositions of the present disclosure, including, for example,calcineurin inhibitors, thalidomide analogues, and any combinationsthereof. Examples of such immunomodulatory drugs include, withoutlimitation, cyclosporine A, voclosporine, tacrolimus, pimecrolimus,thalidomide, lenalidomide, and pomalidomide.

In some embodiments, the pharmaceutical composition comprises the one ormore immunomodulatory drugs at a concentration between 0.0001% and 5%weight per weight (w/w). For example, the pharmaceutical composition maycomprise the one or more immunomodulatory drugs at a concentration fromabout 0.0001% to about 5%, from about 0.0001% to about 4%, from about0.0001% to about 3%, from about 0.0001% to about 2%, from about 0.0001%to about 1%, from about 0.0001% to about 0.5%, from about 0.0001% toabout 0.1%, from about 0.0001% to about 0.05%, from about 0.0001% toabout 0.01%, from about 0.0001% to about 0.005%, from about 0.0001% toabout 0.001%, from about 0.0001% to about 0.0005%, from about 0.0005% toabout 5%, from about 0.0005% to about 4%, from about 0.0005% to about3%, from about 0.0005% to about 2%, from about 0.0005% to about 1%, fromabout 0.0005% to about 0.5%, from about 0.0005% to about 0.1%, fromabout 0.0005% to about 0.05%, from about 0.0005% to about 0.01%, fromabout 0.0005% to about 0.005%, from about 0.0005% to about 0.001%, fromabout 0.001% to about 5%, from about 0.001% to about 4%, from about0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% toabout 1%, from about 0.001% to about 0.5%, from about 0.001% to about0.1%, from about 0.001% to about 0.05%, from about 0.001% to about0.01%, from about 0.001% to about 0.005%, from about 0.005% to about 5%,from about 0.005% to about 4%, from about 0.005% to about 3%, from about0.005% to about 2%, from about 0.005% to about 1%, from about 0.005% toabout 0.5%, from about 0.005% to about 0.1%, from about 0.005% to about0.05%, from about 0.005% to about 0.01%, from about 0.01% to about 5%,from about 0.01% to about 4%, from about 0.01% to about 3%, from about0.01% to about 2%, from about 0.01% to about 1%, from about 0.01% toabout 0.5%, from about 0.01% to about 0.1%, from about 0.01% to about0.05%, from about 0.05% to about 5%, from about 0.05% to about 4%, fromabout 0.05% to about 3%, from about 0.05% to about 2%, from about 0.05%to about 1%, from about 0.05% to about 0.5%, from about 0.05% to about0.1%, from about 0.1% to about 5%, from about 0.1% to about 4%, fromabout 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% toabout 1%, from about 0.1% to about 0.5%, from about 0.5% to about 5%,from about 0.5% to about 4%, from about 0.5% to about 3%, from about0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about5%, from about 1% to about 4%, from about 1% to about 3%, from about 1%to about 2%, from about 2% to about 5%, from about 2% to about 4%, fromabout 2% to about 3%, from about 3% to about 5%, from about 3% to about4%, or from about 4% to about 5% w/w. In some embodiments, thepharmaceutical composition comprises the one or more immunomodulatorydrugs at any of a concentration of about 0.0001%, 0.0005%, 0.001%,0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%,0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%,0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%,0.95%, 1%, 2%, 3%, 4%, or 5% w/w.

Integrin Antagonists as Additional Lipophilic Compounds

In some embodiments, a pharmaceutical composition of the presentdisclosure further comprises a therapeutically effective amount of oneor more integrin antagonists. In some embodiments, the pharmaceuticalcomposition comprises two or more (e.g., two or more, three or more,four or more, five or more, etc.) integrin antagonists. Any suitableintegrin antagonist known in the art may be used in the pharmaceuticalcompositions of the present disclosure, including, for example,lifitegrast, GW559090, ester derivatives thereof, and any combinationsthereof. In some embodiments, the pharmaceutical composition comprisesGW559090 (See Krauss et al. Invest. Ophthalmol. Vis. Sci.2015;56(10):5888-95).

In some embodiments, the pharmaceutical composition comprises the one ormore integrin antagonists at a concentration between 0.0001% and 10%weight per weight (w/w). For example, the pharmaceutical composition maycomprise the one or more integrin antagonists at a concentration fromabout 0.0001% to about 10%, from about 0.0001% to about 9%, from about0.0001% to about 8%, from about 0.0001% to about 7%, from about 0.0001%to about 6%, from about 0.0001% to about 5%, from about 0.0001% to about4%, from about 0.0001% to about 3%, from about 0.0001% to about 2%, fromabout 0.0001% to about 1%, from about 0.0001% to about 0.5%, from about0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about0.0001% to about 0.01%, from about 0.0001% to about 0.005%, about0.0001% to about 0.001%, about 0.0001% to about 0.0005%, about 0.0005%to about 10%, from about 0.0005% to about 9%, from about 0.0005% toabout 8%, from about 0.0005% to about 7%, from about 0.0005% to about6%, from about 0.0005% to about 5%, from about 0.0005% to about 4%, fromabout 0.0005% to about 3%, from about 0.0005% to about 2%, from about0.0005% to about 1%, from about 0.0005% to about 0.5%, from about0.0005% to about 0.1%, from about 0.0005% to about 0.05%, from about0.0005% to about 0.01%, from about 0.0005% to about 0.005%, about0.0005% to about 0.001%, about 0.001% to about 10%, from about 0.001% toabout 9%, from about 0.001% to about 8%, from about 0.001% to about 7%,from about 0.001% to about 6%, from about 0.001% to about 5%, from about0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% toabout 2%, from about 0.001% to about 1%, from about 0.001% to about0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%,from about 0.001% to about 0.01%, from about 0.001% to about 0.005%,from about 0.01% to about 10%, from about 0.01% to about 9%, from about0.01% to about 8%, from about 0.01% to about 7%, from about 0.01% toabout 6%, from about 0.01% to about 5%, from about 0.01% to about 4%,from about 0.01% to about 3%, from about 0.01% to about 2%, from about0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% toabout 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about10%, from about 0.05% to about 9%, from about 0.05% to about 8%, fromabout 0.05% to about 7%, from about 0.05% to about 6%, from about 0.05%to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%,from about 0.05% to about 2%, from about 0.05% to about 1%, from about0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% toabout 10%, from about 0.1% to about 9%, from about 0.1% to about 8%,from about 0.1% to about 7%, from about 0.1% to about 6%, from about0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about0.1% to about 0.5%, from about 0.5% to about 10%, from about 0.5% toabout 9%, from about 0.5% to about 8%, from about 0.5% to about 7%, fromabout 0.5% to about 6%, from about 0.5% to about 5%, from about 0.5% toabout 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, fromabout 0.5% to about 1%, from about 1% to about 10%, from about 1% toabout 9%, from about 1% to about 8%, from about 1% to about 7%, fromabout 1% to about 6%, from about 1% to about 5%, from about 1% to about4%, from about 1% to about 3%, from about 1% to about 2%, from about 2%to about 10%, from about 2% to about 9%, from about 2% to about 8%, fromabout 2% to about 7%, from about 2% to about 6%, from about 2% to about5%, from about 2% to about 4%, from about 2% to about 3%, from about 3%to about 10%, from about 3% to about 9%, from about 3% to about 8%, fromabout 3% to about 7%, from about 3% to about 6%, from about 3% to about5%, from about 3% to about 4%, from about 4% to about 10%, from about 4%to about 9%, from about 4% to about 8%, from about 4% to about 7%, fromabout 4% to about 6%, from about 4% to about 5%, from about 5% to about10%, from about 5% to about 9%, from about 5% to about 8%, from about 5%to about 7%, from about 5% to about 6%, from about 6% to about 10%, fromabout 6% to about 9%, from about 6% to about 8%, from about 6% to about7%, from about 7% to about 10%, from about 7% to about 9%, from about 7%to about 8%, from about 8% to about 10%, from about 8% to about 9%, orfrom about 9% to about 10% w/w. In some embodiments, the pharmaceuticalcomposition comprises the one or more integrin antagonists at any of aconcentration of about 0.0001%, 0.0005%, 0.001%, 0.005%, 0.01%, 0.02%,0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%,0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%,0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.25%,1.5%, 1.75%, 2%, 2.25%, 2.5%, 2.75%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%,6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, or 10% w/w.

Anti-Inflammatory Agents as Additional Lipophilic Compounds

In some embodiments, a pharmaceutical composition of the presentdisclosure further comprises a therapeutically effective amount of oneor more anti-inflammatory agents. In some embodiments, thepharmaceutical composition comprises two or more (e.g., two or more,three or more, four or more, five or more, etc.) anti-inflammatoryagents. Any suitable anti-inflammatory agent known in the art may beused in the pharmaceutical compositions of the present disclosure,including, for example, omega 3 fatty acids, non-steroidalanti-inflammatory drugs (NSAIDS), and any combinations thereof. Examplesof suitable omega 3 fatty acids may include, without limitation,eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), alpha-linolenicacid (ALA), and any combinations thereof. Examples of suitable NSAIDSmay include, without limitation, bromfenac, diclofenac, indomethacin,flurbiprofen, ketorolac, nepafenac, and any combinations thereof.

In some embodiments, the pharmaceutical composition comprises the one ormore anti-inflammatory agents at a concentration between 0.0001% and 5%weight per weight (w/w). For example, the pharmaceutical composition maycomprise the one or more anti-inflammatory agents at a concentrationfrom about 0.0001% to about 5%, from about 0.0001% to about 4%, fromabout 0.0001% to about 3%, from about 0.0001% to about 2%, from about0.0001% to about 1%, from about 0.0001% to about 0.5%, from about0.0001% to about 0.1%, from about 0.0001% to about 0.05%, from about0.0001% to about 0.01%, from about 0.0001% to about 0.005%, from about0.0001% to about 0.001%, from about 0.0001% to about 0.0005%, from about0.0005% to about 5%, from about 0.0005% to about 4%, from about 0.0005%to about 3%, from about 0.0005% to about 2%, from about 0.0005% to about1%, from about 0.0005% to about 0.5%, from about 0.0005% to about 0.1%,from about 0.0005% to about 0.05%, from about 0.0005% to about 0.01%,from about 0.0005% to about 0.005%, from about 0.0005% to about 0.001%,from about 0.001% to about 5%, from about 0.001% to about 4%, from about0.001% to about 3%, from about 0.001% to about 2%, from about 0.001% toabout 1%, from about 0.001% to about 0.5%, from about 0.001% to about0.1%, from about 0.001% to about 0.05%, from about 0.001% to about0.01%, from about 0.001% to about 0.005%, from about 0.005% to about 5%,from about 0.005% to about 4%, from about 0.005% to about 3%, from about0.005% to about 2%, from about 0.005% to about 1%, from about 0.005% toabout 0.5%, from about 0.005% to about 0.1%, from about 0.005% to about0.05%, from about 0.005% to about 0.01%, from about 0.01% to about 5%,from about 0.01% to about 4%, from about 0.01% to about 3%, from about0.01% to about 2%, from about 0.01% to about 1%, from about 0.01% toabout 0.5%, from about 0.01% to about 0.1%, from about 0.01% to about0.05%, from about 0.05% to about 5%, from about 0.05% to about 4%, fromabout 0.05% to about 3%, from about 0.05% to about 2%, from about 0.05%to about 1%, from about 0.05% to about 0.5%, from about 0.05% to about0.1%, from about 0.1% to about 5%, from about 0.1% to about 4%, fromabout 0.1% to about 3%, from about 0.1% to about 2%, from about 0.1% toabout 1%, from about 0.1% to about 0.5%, from about 0.5% to about 5%,from about 0.5% to about 4%, from about 0.5% to about 3%, from about0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about5%, from about 1% to about 4%, from about 1% to about 3%, from about 1%to about 2%, from about 2% to about 5%, from about 2% to about 4%, fromabout 2% to about 3%, from about 3% to about 5%, from about 3% to about4%, or from about 4% to about 5% w/w. In some embodiments, thepharmaceutical composition comprises the one or more anti-inflammatoryagents at any of a concentration of about 0.0001%, 0.0005%, 0.001%,0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%,0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%, 0.275%, 0.3%, 0.35%,0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%,0.95%, 1%, 2%, 3%, 4%, or 5% w/w.

Anti-Glaucoma Drugs and Ocular Anti-hypertension Agents and asAdditional Lipophilic Compounds

In some embodiments, a pharmaceutical composition of the presentdisclosure further comprises a therapeutically effective amount of oneor more anti-glaucoma drugs or ocular anti-hypertension agents. In someembodiments, the pharmaceutical composition comprises two or more (e.g.,two or more, three or more, four or more, five or more, etc.)anti-glaucoma drugs or ocular anti-hypertension agents. Any suitableanti-glaucoma drug or ocular anti-hypertension agent known in the artmay be used in the pharmaceutical compositions of the presentdisclosure, including, for example, prostaglandin analogs, betablockers, alpha-2 agonists, carbonic anhydrase inhibitors, Rho kinaseinhibitors, and any combinations thereof. Examples of suitableprostaglandin analogs may include, without limitiation, bimatoprost,latanoprost, travoprost, tafluprost, latanoprostene-bunod, and anycombinations thereof. Examples of suitable beta blockers may include,without limitiation, timolol, betaxolol, levobunolol, metipranolol, andany combinations thereof. Examples of suitable alpha-2 agonists mayinclude brimonidine, clonidine, apraclonidine, and any combinationsthereof. Examples of suitable carbonic anhydrase inhibitors may include,without limitiation, dorzolamide, brinzolamide, acetazolamide,methazolamide, and any combinations thereof. Examples of suitable Rhokinase inhibitors may include, without limitiation, netarsudil, and anycombinations thereof.

In some embodiments, the pharmaceutical composition comprises the one ormore anti-glaucoma drug or ocular anti-hypertension agent at aconcentration between 0.0001% and 10% weight per weight (w/w). Forexample, the pharmaceutical composition may comprise the one or moreanti-glaucoma drug or ocular anti-hypertension agent at a concentrationfrom about 0.0001% to about 10%, from about 0.0001% to about 9%, fromabout 0.0001% to about 8%, from about 0.0001% to about 7%, from about0.0001% to about 6%, from about 0.0001% to about 5%, from about 0.0001%to about 4%, from about 0.0001% to about 3%, from about 0.0001% to about2%, from about 0.0001% to about 1%, from about 0.0001% to about 0.5%,from about 0.0001% to about 0.1%, from about 0.0001% to about 0.05%,from about 0.0001% to about 0.01%, from about 0.0001% to about 0.005%,about 0.0001% to about 0.001%, about 0.0001% to about 0.0005%, about0.0005% to about 10%, from about 0.0005% to about 9%, from about 0.0005%to about 8%, from about 0.0005% to about 7%, from about 0.0005% to about6%, from about 0.0005% to about 5%, from about 0.0005% to about 4%, fromabout 0.0005% to about 3%, from about 0.0005% to about 2%, from about0.0005% to about 1%, from about 0.0005% to about 0.5%, from about0.0005% to about 0.1%, from about 0.0005% to about 0.05%, from about0.0005% to about 0.01%, from about 0.0005% to about 0.005%, about0.0005% to about 0.001%, about 0.001% to about 10%, from about 0.001% toabout 9%, from about 0.001% to about 8%, from about 0.001% to about 7%,from about 0.001% to about 6%, from about 0.001% to about 5%, from about0.001% to about 4%, from about 0.001% to about 3%, from about 0.001% toabout 2%, from about 0.001% to about 1%, from about 0.001% to about0.5%, from about 0.001% to about 0.1%, from about 0.001% to about 0.05%,from about 0.001% to about 0.01%, from about 0.001% to about 0.005%,from about 0.01% to about 10%, from about 0.01% to about 9%, from about0.01% to about 8%, from about 0.01% to about 7%, from about 0.01% toabout 6%, from about 0.01% to about 5%, from about 0.01% to about 4%,from about 0.01% to about 3%, from about 0.01% to about 2%, from about0.01% to about 1%, from about 0.01% to about 0.5%, from about 0.01% toabout 0.1%, from about 0.01% to about 0.05%, from about 0.05% to about10%, from about 0.05% to about 9%, from about 0.05% to about 8%, fromabout 0.05% to about 7%, from about 0.05% to about 6%, from about 0.05%to about 5%, from about 0.05% to about 4%, from about 0.05% to about 3%,from about 0.05% to about 2%, from about 0.05% to about 1%, from about0.05% to about 0.5%, from about 0.05% to about 0.1%, from about 0.1% toabout 10%, from about 0.1% to about 9%, from about 0.1% to about 8%,from about 0.1% to about 7%, from about 0.1% to about 6%, from about0.1% to about 5%, from about 0.1% to about 4%, from about 0.1% to about3%, from about 0.1% to about 2%, from about 0.1% to about 1%, from about0.1% to about 0.5%, from about 0.5% to about 10%, from about 0.5% toabout 9%, from about 0.5% to about 8%, from about 0.5% to about 7%, fromabout 0.5% to about 6%, from about 0.5% to about 5%, from about 0.5% toabout 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, fromabout 0.5% to about 1%, from about 1% to about 10%, from about 1% toabout 9%, from about 1% to about 8%, from about 1% to about 7%, fromabout 1% to about 6%, from about 1% to about 5%, from about 1% to about4%, from about 1% to about 3%, from about 1% to about 2%, from about 2%to about 10%, from about 2% to about 9%, from about 2% to about 8%, fromabout 2% to about 7%, from about 2% to about 6%, from about 2% to about5%, from about 2% to about 4%, from about 2% to about 3%, from about 3%to about 10%, from about 3% to about 9%, from about 3% to about 8%, fromabout 3% to about 7%, from about 3% to about 6%, from about 3% to about5%, from about 3% to about 4%, from about 4% to about 10%, from about 4%to about 9%, from about 4% to about 8%, from about 4% to about 7%, fromabout 4% to about 6%, from about 4% to about 5%, from about 5% to about10%, from about 5% to about 9%, from about 5% to about 8%, from about 5%to about 7%, from about 5% to about 6%, from about 6% to about 10%, fromabout 6% to about 9%, from about 6% to about 8%, from about 6% to about7%, from about 7% to about 10%, from about 7% to about 9%, from about 7%to about 8%, from about 8% to about 10%, from about 8% to about 9%, orfrom about 9% to about 10% w/w. In some embodiments, the pharmaceuticalcomposition comprises the one or more anti-glaucoma drug or ocularanti-hypertension agent at any of a concentration of about 0.0001%,0.0005%, 0.001%, 0.005%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%,0.07%, 0.08%, 0.09%, 0.1%, 0.125%, 0.15%, 0.175%, 0.2%, 0.225%, 0.25%,0.275%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%,0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.25%, 1.5%, 1.75%, 2%, 2.25%, 2.5%,2.75%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%,9.5%, or 10% w/w.

II. Methods

Certain aspects of the present disclosure relate to methods of providingprophylactic, palliative, and/or therapeutic relief of one or more signsor symptoms of an ocular disease (e.g., an ocular inflammatorycondition, bacterial infection, or glaucoma) comprising administering atherapeutically effective amount of any of the pharmaceuticalcompositions of the present disclosure to a subject in need thereof. Insome embodiments, the present disclosure relates to methods of treatingan ocular disease (e.g., an ocular inflammatory condition, bacterialinfection, or glaucoma) comprising administering a therapeuticallyeffective amount of any of the pharmaceutical compositions of thepresent disclosure to a subject in need thereof. In some embodiments,the subject has, or is at risk of developing an ocular disease (e.g., anocular inflammatory condition, bacterial infection, or glaucoma).

In some embodiments, the lipid structures of the eyelid (e.g., meibomianglands, meibum, other fatty tissues) serve as drug depots for theperi-ocularly delivered pharmaceutical compositions provided herein withthe meibum becoming a drug delivery vehicle.

In some embodiments, the subject is a non-human animal, including,without limitation, domesticated animals (e.g., cows, sheep, cats, dogs,horses, etc.), non-human primates (e.g., monkeys), rabbits, and rodents(e.g., mice, hamsters, rats, etc.). In some embodiments, the subject isa human. In some embodiments, the subject suffers from one or more(e.g., one or more, two or more, three or more, four or more, five ormore, etc.) ocular diseases and/or conditions. Examples of oculardiseases and/or conditions may include, without limitation, inflammationof the peri-ocular glands, meibomitis, dry eye disease, allergic eyedisease, topical preservative toxicity, xerophthalmia, loss ofhomeostasis of the tear film, tear film instability and hyperosmolarity,ocular surface inflammation and damage, neuronal sensory abnormalities,meibomian gland dysfunction, exacerbated inflammatory ocular surfacedisease, phlyctenular keratitis, chalazion, anterior blepharitis,posterior blepharitis, bacterial infection, glaucoma, ocularhypertension, and any combinations thereof.

In some embodiments, a pharmaceutical composition of the presentdisclosure is topically administered to the subject. As used herein,“topically administered”, “topical administration”, or “topicallyadministering” refers to the delivery of a composition to a subject bycontacting, directly or otherwise, a formulation comprising thecomposition to a portion of the skin of a subject. The term mayencompass several routes of administration including, but not limitedto, topical and transdermal. Topical administration may be used as ameans to deliver a composition to the epidermis or dermis of a subject,or to specific strata thereof.

In some embodiments, a pharmaceutical composition of the presentdisclosure is topically administered to an external portion of one orall eyelids of a subject (including the upper lateral region of one orboth orbits of the subject). In some embodiments, the pharmaceuticalcomposition is topically administered to the external portion of theupper and/or lower eyelid of one or both eyes of the subject. In someembodiments, the pharmaceutical composition is not administered directlyand/or indirectly, to the ocular surface.

In some embodiments, a pharmaceutical composition of the presentdisclosure is topically administered to an external portion of one orall eyelids of a subject (including the upper lateral region of one orboth orbits of the subject) in order to deliver lipophilic compounds(e.g., steroids) to one or more meibomian glands of the subject. In someembodiments, one or more components (e.g., a steroid) in thepharmaceutical composition are delivered to the ocular surface of asubject via the one or more meibomian glands. In some embodiments, oneor more components (e.g., a steroid) in the pharmaceutical compositionare delivered to the ocular surface of a subject via the meibum.

In some embodiments, a pharmaceutical composition of the presentdisclosure is administered one or more (e.g., one or more, two or more,three or more, four or more, five or more, six or more, seven or more,eight or more, nine or more, ten or more, etc.) times per day. In someembodiments, a pharmaceutical composition of the present disclosure isadministered for one, two, three, four, five, six, seven or moreconsecutive days. In some embodiments, a pharmaceutical composition ofthe present disclosure is administered for one, two, three, four, five,six, seven or more non-consecutive days. In some embodiments, apharmaceutical composition of the present disclosure is administered forone, two, three, four, five, six, seven, eight, nine, 10, 11, 12 or moreconsecutive weeks. In some embodiments, a pharmaceutical composition ofthe present disclosure is administered for one, two, three, four, five,six, seven, eight, nine, 10, 11, 12 or more non-consecutive weeks. Insome embodiments, a pharmaceutical composition of the present disclosureis administered for one, two, three, four, five, six, seven, eight,nine, 10, 11, 12 or more consecutive months. In some embodiments, apharmaceutical composition of the present disclosure is administered forone, two, three, four, five, six, seven, eight, nine, 10, 11, 12 or morenon-consecutive months. In some embodiments, treatment is initiated witha loading dose followed by dose tapering. In some embodiments, treatmentis initiated with a loading dose, followed by sustained treatment with alower dose.

In some embodiments, the exposure level of the lipophilic compound inthe eyelids, bulbar conjunctiva, cornea, iris/ciliary body (ICB), and/oraqueous humor (AQH) remains constant or substantially constant for up to24 hours after the final pen-ocular dose application. In someembodiments, the concentration of the lipophilic compound in one or morecompartments selected from the group consisting of the eyelids, bulbarconjunctiva, cornea, iris/ciliary body (ICB), and aqueous humor (AQH)differ by less than 50%, less than 40%, less than 30%, less than 25%,less than 20%, less than 15%, less than 10%, less than 9%, less than 8%,less than 7%, less than 6%, less than 5%, less than 4%, less than 3%,less than 2%, or less than 1% when comparing the concentration at 2hours and 24 hours after the final peri-ocular dose application. In someembodiments, the concentration of the lipophilic compound in one or morecompartments selected from the group consisting of the eyelids, bulbarconjunctiva, cornea, iris/ciliary body (ICB), and aqueous humor (AQH) at24 hours after the final pen-ocular dose application is within 50%, 40%,30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of theconcentration of the lipophilic compound at 2 hours after the finalperi-ocular dose application. In some embodiments, the concentration ofthe lipophilic compound in the eyelids at 24 hours after the finalpen-ocular dose application is within 50%, 40%, 30%, 25%, 20%, 15%, 10%,9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the concentration of thelipophilic compound at 2 hours after the final peri-ocular doseapplication. In some embodiments, the concentration of the lipophiliccompound in the eyelids at 24 hours after the final pen-ocular doseapplication is not less than 50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%,7%, 6%, 5%, 4%, 3%, 2%, or 1% of the concentration of the lipophiliccompound at 2 hours after the final pen-ocular dose application. In someembodiments, the concentration of the lipophilic compound in one or morecompartments selected from the group consisting of the eyelids, bulbarconjunctiva, cornea, iris/ciliary body (ICB), and aqueous humor (AQH) at24 hours after the final peri-ocular dose application is not less than50%, 40%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1%of the concentration of the lipophilic compound at 2 hours after thefinal pen-ocular dose application. In some embodiments, theconcentration of the lipophilic compound in the eyelids at 24 hoursafter the final pen-ocular dose application is not less than 25%, 20%,15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the concentration ofthe lipophilic compound at 2 hours after the final pen-ocular doseapplication.

In some embodiments, topical administration of the pharmaceuticalcomposition as described herein provides prophylactic, palliative,and/or therapeutic relief of one or more signs of an ocular disease in asubject. In some embodiments, topical administration of thepharmaceutical composition as described herein reduces or eliminates oneor more signs of an ocular disease in a subject. Examples of signs orsymptoms of an ocular disease may include, without limitation, eyeand/or eyelid margin redness, watery eyes, dry eyes, itching, stinging,or burning sensation of the eyes or orbits, blurry vision, difficultywith nighttime driving, night blindness, conjunctival xerosis, cornealxerosis, corneal ulcers, Bitot's spots, eye fatigue, foreign bodysensation in the eye, light sensitivity, stringy mucus in or around theeyes, swelling of the conjunctiva and/or eyelids, dry, flaky, and/ordamaged skin of the eyelids and/or orbits, eyelids that appear greasy,eyelid sticking, abnormal eyelash growth, loss of eyelashes, discomfortor pain of the eyes, eyelids, and/or orbits, chronic and episodicpunctate keratopathy, filamentary keratopathy, recurrent cornealerosion, persistent epithelial defect, corneal melt, ocular surfacefailure, blepharospasm, mucopurulent discharge, appearance of achalazion, and any combinations thereof.

In some embodiments, topical administration of the pharmaceuticalcomposition as described herein reduces inflammation in one or morepen-orbital glands (e.g., one or more, two or more, or all three of theMeibomian, lacrimal, and/or accessory lacrimal glands) of a subject. Insome embodiments, topical administration of the pharmaceuticalcomposition as described herein reduces inflammation in one or morepen-orbital glands by about 5%, about 10%, about 15%, about 20%, about25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%,about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about90%, about 95%, or about 99% relative to the inflammation observed priorto administration of the pharmaceutical composition. In someembodiments, topical administration of the pharmaceutical compositionreduces inflammation in one or more peri-orbital glands by about 1-fold,about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold,about 7-fold, about 8-fold, about 9-fold, about 10-fold, about 100-fold,or about 1000-fold relative to the inflammation observed prior toadministration of the pharmaceutical composition. In some embodiments,topical administration of the pharmaceutical composition as describedherein eliminates inflammation in one or more pen-orbital glands of thesubject. Methods of measuring peri-orbital gland inflammation are knownin the art, including, for example, using laser in vivo confocalmicroscopy (IVCM) (See Qazi et al. Investigative Ophthalmology & VisualScience March 2012, Vol.53, 593).

In some embodiments, topical administration (e.g., prolonged/protractedadministration) of the pharmaceutical composition as described hereindoes not result in an adverse event in the subject. Examples of adverseevents may include, but are not limited to, elevated intraocularpressure, the formation or worsening of cataracts, ocular infection, andany combinations there. In some embodiments, topical administration ofthe pharmaceutical composition does not increase/elevate intraocularpressure in the subject.

In some embodiments, the lipophilic compound is not deliveredsystemically to the subject by the administration of the pharmaceuticalcomposition. In some embodiments, the lipophilic compound is notdelivered to a tear or tear duct of the subject by the administration ofthe pharmaceutical composition. In some embodiments, the lipophiliccompound is not delivered directly to an ocular surface of the subjectby the administration of the pharmaceutical composition.

III. Article of Manufacture or Kit

Certain aspects of the present disclosure relate to an article ofmanufacture or kit comprising one or more of the pharmaceuticalcompositions described herein. In some embodiments, the article ofmanufacture or kit comprises a label and/or package insert comprisinginstructions for use of the one or more pharmaceutical compositions. Insome embodiments, the one or more pharmaceutical compositions areprovided in a container. In some embodiments, the components of thepharmaceutical composition are provided in a single container, or in twoor more separate containers. In some embodiments, the article ofmanufacture or kit comprises the container(s) and a label or packageinsert on or associated with the container(s). Suitable containers mayinclude, for example, tubes, bottles, vials, bags, etc. The containermay be formed from a variety of suitable materials such as glass,plastic (such as polyvinyl chloride, polyolefin, or polyethylene),metal, and/or metal alloy (such as stainless steel). The article ofmanufacture or kit may further include other materials desirable from acommercial and user standpoint, including buffers, diluents, filters,syringes, applicators, and the like.

The foregoing written description is considered to be sufficient toenable one skilled in the art to practice the present disclosure. Thefollowing Examples are offered for illustrative purposes only, and arenot intended to limit the scope of the present disclosure in any way.Indeed, various modifications of the present disclosure in addition tothose shown and described herein will become apparent to those skilledin the art from the foregoing description and fall within the scope ofthe appended claims.

IV. Definitions

Before describing the present disclosure in detail, it is to beunderstood that this present disclosure is not limited to particularcompositions or biological systems, which can, of course, vary. It isalso to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting.

As used herein, the singular forms “a,” “an,” and “the” include pluralreference unless the context clearly indicates otherwise. Thus, forexample, reference to “a molecule” optionally includes a combination oftwo or more such molecules, and the like.

As used herein, the term “about” refers to the usual error range for therespective value readily known to the skilled person in this technicalfield. Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse.

As used herein, the term “and/or”, as in a phrase such as “A and/or B”,is intended to include both A and B; A or B; A (alone); and B (alone).Likewise, as used herein, the term “and/or”, as in a phrase such as “A,B, and/or C”, is intended to encompass each of the followingembodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; Aand B; B and C; A (alone); B (alone); and C (alone).

As used herein, the terms “individual”, “patient”, or “subject” refer toa mammal. Mammals include, but are not limited to, domesticated animals(e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans andnon-human primates such as monkeys), rabbits, and rodents (e.g., mice,hamsters, and rats). In some embodiments, the individual, patient, orsubject is a human.

As used herein, the term “pharmaceutical formulation” refers to apreparation which is in such form as to permit the biological activityof an active ingredient contained therein to be effective, and whichcontains no additional components which are unacceptably toxic to asubject to which the formulation would be administered.

As used herein, the term “pharmaceutically acceptable carrier” refers toan ingredient in a pharmaceutical formulation, other than an activeingredient, which is nontoxic to a subject.

As used herein, the term “prevention” includes providing prophylaxiswith respect to occurrence or recurrence of one or more signs orsymptoms of a disorder in an individual. An individual may bepredisposed to a disorder, susceptible to a disorder, or at risk ofdeveloping a disorder, but has not yet been diagnosed with the disorder.

As used herein, an individual “at risk” of developing a disorder may ormay not have detectable disease or symptoms of disease, and may or maynot have displayed detectable disease or symptoms of disease prior tothe treatment methods described herein. “At risk” denotes that anindividual has one or more risk factors, which are measurable parametersthat correlate with development of the disorder, as known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disorder than an individual without one ormore of these risk factors.

As used herein, the term “treatment” refers to clinical interventiondesigned to alter the natural course of the individual or cell beingtreated during the course of clinical pathology. Desirable effects oftreatment include, for example, decreasing the rate of diseaseprogression, ameliorating or palliating the disease state, and improvedprognosis. An individual is successfully “treated”, for example, if oneor more signs or symptoms associated with the disorder are mitigated oreliminated. For example, an individual is successfully “treated” if oneor more symptoms associated with an inflammatory disease are mitigatedor eliminated, including, but are not limited to, decreasing symptomsresulting from the disease, increasing the quality of life of thosesuffering from the disease, decreasing the dose of other medicationsrequired to treat the disease, and/or delaying the progression of thedisease.

An “effective amount” refers to at least an amount effective, at dosagesand for periods of time necessary, to achieve the desired or indicatedeffect, including a therapeutic or prophylactic result. An effectiveamount can be provided in one or more administrations.

A “therapeutically effective amount” is at least the minimumconcentration required to effect a measurable improvement of one or moresigns or symptoms of a particular disorder. A therapeutically effectiveamount herein may vary according to factors such as the disease state,age, sex, and weight of the patient. A therapeutically effective amountis also one in which any detrimental effects of the treatment areoutweighed by the therapeutically beneficial effects.

The term “pen-ocular” refers to the area surrounding the eyeball butwithin the orbit, including eyelids and lateral regions of the orbit.

The “pen-orbital glands” are the glands in the area around the eyeballincluding, for example, the meibomian, lacrimal, and/or accessorylacrimal glands.

EXAMPLES Example 1 Effect of Treatment with the Compound of Formula I onIntraocular Pressure (IOP) and Tear Formation

The compound of Formula I is a fluorinated glucocorticoid withanti-inflammatory activity (See U.S. Pat. No. 7,288,536). The compoundof Formula I showed close to full agonism in a variety of human in vitroassays of glucocorticoid receptor-mediated transrepression activity, andshowed a partial response in a number of assays of glucocorticoidreceptor-mediated transactivation. In vivo, the compound of Formula Idisplayed potent anti-inflammatory activity following intratrachealdosing in models of lung inflammation in the mouse and rat, and showedsimilar activity to fluticasone propionate (FP) in topical delayed typehypersensitivity ear inflammation, tyrosine aminotransferase induction,and chronic house dust mite models in the mouse. Interleukin-1β (IL-1β)and Tumour Necrosis Factor α (TNFα) stimulate the release of thepro-inflammatory cytokines Interleukin-6 (IL-6) and Interleukin-8 (IL-8)from a variety of cell types through activation of the NFκB pathway. FPand the compound of Formula I are able to potently and efficientlytransrepress this activation across a number of systems (A549, HeLa,MG63, 16HBE, and H9 cell lines). These are the same inflammatory markerselevated in patients with aberrant inflammation of the peri-ocularglands (DEWS, 2007).

To test the effect of the compound of Formula I on intraocular pressure(IOP), eight female cynomolgus monkeys with unilateral (OS) ocularhypertension induced by prior photocoagulation (laser) procedure to thetrabecular meshwork (TM) were used at an age between 11 and 14 years atthe start of the study. Laser induced ocular hypertension had beencreated at least 9 years earlier in the study animals. Animals andtreatments were randomized according to a 4×4 replications Williams-typeLatin Square design layout. Following random assignment of a numberbetween 1 and 8, the eight primates were randomized two each into fourtreatment groups (A-D), with treatments masked for the investigatorsuntil all data had been collected and entered into a database. Thetreatment groups A-D were as follows: the compound of Formula I (10mg/mL suspension in placebo vehicle), mapracorat (10 mg/mL suspension inplacebo vehicle), Maxidex® (1 mg/mL), and placebo control.

Topical bilateral treatment occurred in a randomized, masked crossoverformat. All four treatments were investigated in parallel in two animalsper treatment group during each 4-week treatment period. The assigned,masked formulation (A, B, C, or D) was administered to both eyes (OU) ina 25 μL volume three times daily (TID; at 8:30 am, 1 pm, and 5 pm).Treatment periods were separated by a 4-week washout/recovery periodwithout topical treatment. The first period (period 1) was preceded by a2-week run-in period during which all animals received placebo topicallyTID.

Conscious animals were seated in custom-designed chairs, and IOP wasmeasured with a pneumatonometer (Classic 30, Reichert Depew) aftertopical application of proparacaine hydrochloride (0.13%) in both eyes(FIG. 1). Two to three measurements were taken for each eye andaveraged. Data was stored and archived. During run-in and treatmentperiods, diurnal IOP was determined two times per week at approximately8:30 am, 1 pm, and 5 pm. For each animal bilateral tonometry wasfollowed immediately by topical instillation of the appropriate drugformulation A, B, C, or D. During washout periods, diurnal IOP wasmeasured once per week in both eyes at approximately 8:30 am, 1 pm, and5 pm. Surprisingly, topical treatment with the compound of Formula Iover 4 weeks did not result in increased TOP in primates (FIG. 1). Infact, IOP in eyes treated with the compound of Formula I was similar toeyes treated with vehicle alone, and was significantly lower thandexamethasone treatment, demonstrating that the compound of Formula Idoes not produce the IOP increase typically associated with topicalcorticosteroids (e.g., dexamethasone).

Next, the effect on tear formation of treatment with the compound ofFormula I was examined. Rabbits were placed in a restraining device, andatropine sulfate 1% ophthalmic solution (30 μL) was instilled into thelower conjunctival sac of each eye four times per day. Fifteen minutesafter the administration of each dose of atropine sulfate, each eyereceived 30 μL of eye drops containing the active ingredient, vehicle,or saline. Tear volume was then evaluated by the Schirmer test (FIG. 2).Schirmer strips were carefully placed in the posterior (i.e., temporal)lower fornix for 60 seconds, and the wetted area was read in millimetersas an index of tear volume. Surprisingly, when administered to theocular surface in vivo for seven days, the compound of Formula Iprevented a decrease in tear formation similar to topical dexamethasonein a model of dry eye disease (FIG. 2).

Taken together, the data presented herein demonstrate that the compoundof Formula I is equally effective at treating dry eye disease as topicalcorticosteroids, such as dexamethasone, but does not induce the negativeside effect of increased IOP typically associated with administration ofcorticosteroid compounds to the eye. The absence of effect on IOPindicates an improved, desirable safety profile of the compound ofFormula I, as compared to other steroids such as dexamethasone.

Example 2 Determining Characteristics of a Peri-Ocular Cream Formulation

The following active pharmaceutical ingredients (API) were mixed withcream vehicle for the preparation of creams containing 2% API by weightfor this study and allowed to rest at room temperature for 24 hoursbefore testing. Cyclosporin A (Sample A), loteprednol etabonate (SampleB), dexamethasone (Sample C), ketorolac tromethamine (Sample D),gatifloxacin, USP (Sample E), gentamicin sulfate (Sample F),prednisolone (Sample G), flurbiprofen (Sample H), azithromycindihydrated (Sample J), triamcinolone acetonide (Sample K), anddoxycycline hydrochloride (Sample L). Vehicle cream comprised 48% w/wwhite soft petrolatum, 8% w/w mineral oil, 8% w/w propylene glycol, 6.6%w/w ST-cyclomethicone-5NF, 3.3% w/w emulsifier 10, 2% w/wST-elastomer-10, 0.08% w/w methylparaben, 0.06% w/w sodium phosphatedibasic anhydrous, 0.0546% w/w citric acid anhydrous, 0.02% w/wpropylparaben, and q.s. purified water. The compound of Formula I wasincorporated into a cream with the following final composition: 2% w/wcompound of Formula I, 46% w/w white petrolatum, 8% w/w mineral oil, 8%w/w propylene glycol, 6.6% w/w ST-cyclomethicone-SNF, 3.3% w/wemulsifier 10, 2% w/w ST-elastomer-10, 0.08% w/w methylparaben, 0.06%w/w sodium phosphate dibasic anhydrous, 0.05% w/w citric acid anhydrous,0.02% w/w propylparaben, and q.s. purified water.

Results of the flow visualization study are qualitative and wererecorded by photograph, for each sample and each test condition. Using awide mouth disposable pipette, a small aliquot of 2% API-containingcream at approximately 1 ml was placed into Kimble 1-dram glass vials,15×45 mm. The vial was capped and labeled on the glass vial, A throughL, as referenced in the preceding paragraph. For each test, sample vialswere placed into the thermostatted couette rheometer cup at 37° C., insets of 2 or 3 vials, and equilibrated at 37° C. for a minimum of 10minutes. After 10 minutes, sample glass vials were removed, marked witha red line at the fluid surface or meniscus, inverted and returned tothe 37° C. rheometer cup. At two time periods, 2 minutes and 5 minutes,vials were removed and photographed to document any movement of thecream.

Preliminary measurements with the vehicle cream and the 2% compound ofFormula I cream were made in comparison to a high viscosity polybutenestandard, N62000. The vehicle cream and the 2% compound of Formula Icream showed no discernible flow at 37° C. at the 2 and 5 minute timepoints in contrast to the N62000 high viscosity polymer standard wherebulk flow was observed (FIG. 3A). The same procedure was used for the 2%API-containing experimental cream samples prepared from the elevencompounds listed above and also tested at 37° C. This simple test showsthat none of the eleven prepared 2% API-containing creams exhibited anydiscernible flow under the prescribed test conditions, as shown forthree of the creams in FIG. 3B. In summary, the yield stress at 37° C.is apparently strong enough to prevent flow under the influence ofgravity under the test conditions.

The stress relaxation yield stress test employed a rheometer and a 10%Step Strain Stress Relaxation measurement on a 25 mm cone and plate.This test applies an instantaneous motion as a step strain to thesamples at t=0 and subsequently measures the shear stress relaxation.For Newtonian fluids, the relaxation is immediate. For non-Newtonianfluids, there can be a delayed stress relaxation with distribution ofrelaxation times with relaxation to zero. Non-Newtonian materials withyield stress will show a distribution of relaxation times with anon-zero stress relaxation—or infinite relaxation time. This is theequivalent of the yield stress. Testing was performed at both 25 and 37°C.

Measurements with Ultima white petrolatum were compared with vehiclecream and 2% API-containing creams of the compound of Formula I and theeleven APIs described above. All prepared 2% API creams, vehicle creamand Ultima white petrolatum exhibited yield stresses as determined bythese step strain stress relaxation measurements. There is somevariability in the data. This may be due to the insufficient mixing ofthe API in each vehicle cream, air entrapment during mixing, particlesize of the API used in this study, and other factors. Regardless of thesource of variance, each 2% API-containing cream exhibited a yieldstress. So did vehicle cream and white petrolatum. Curves (some examplesin FIG. 4A-D) very consistently show stress relaxation to a non-zeroshear stress value. Noting that the creams are quite shear sensitive,results are summarized in the following table (Table 1) for each samplein each test at both 25 and 37° C., including Ultima petrolatum; 1-5replicates.

TABLE 1 Sample ID T° C. Yield Stress Values in Units of Pa A 25 10.1 3.010.0 9.5 A 37 3.0 2.3 B 25 15.5 14.6 B 37 3.0 2.0 1.9 C 25 4.2 2.9 C 373.4 1.8 D 25 8.5 3.1 10.5 D 37 2.9 1.4 E 25 17.6 16.9 3.9 E 37 5.0 4.0 F25 4.1 3.1 F 37 3.6 3.5 G 25 3.9 3.2 G 37 1.4 2.7 4.1 H 25 18.5 18.9 5.9H 37 2.0 2.3 J 25 8.5 9.7 4.9 J 37 1.8 2.1 K 25 11.6 7.5 7.2 7.1 19.9 K37 6.9 7.1 L 25 12.9 10.3 4.4 L 37 1.5 1.6 Ultima 25 35.2 30.8 Ultima 3714.7

For comparison, yield stress values (in units of Pa) for the vehiclecream were 4.1, 3.3, 2.9 and 1.0, 1.0, 1.5 at 25 and 37° C.,respectively (3 replicates each). Yield stress values (in units of Pa)for the 2% compound of Formula I cream were 2.2, 2.8 and 1.0, 0.9, 0.9at 25 and 37° C., respectively (2-3 replicates each). For comparison,the stress relaxation function for the high viscosity polybutene N62000standard showed a rapid decay to zero in less than 1 second at roomtemperature.

For all samples, except Samples F and G, the yield stress decreases withincreasing temperature from 25° C. to 37° C. The yield stress of theUltima petrolatum is much higher than the 2% API-containing or vehiclecream samples indicating a more difficult spreadability of the Ultimapetrolatum onto contact surfaces, such as the eyelid. All 2% API creamsshow extensional viscosity behavior and may be strain thickening. Thisis a material property that may contribute to increased cohesiveness oncontact surfaces, further counteracting the influence of gravity andlimiting flow. More importantly, the extensional viscosity may enhancephysical stability preventing sedimentation of active ingredients. Thesedata suggest that all of the cream formulations will facilitateapplication to the intended surfaces (eyelids) compared to an ointment.Because of the lower yield stress of the API-containing creams and thevehicle cream, these formulations will be easier for the consumer to useand apply relative to petrolatum alone. In contrast, a high viscositypolymer such as N62000 is not likely to be suitable for the presentinvention. The data clearly show that the goal to develop a creamformulation that is easy to apply to a contact surface, such as theeyelid, and that does not flow following eyelid application, so as toprevent formulation flowing onto the ocular surface, has been achievedwith the formulations of this invention.

Example 3 Skin Penetration of a Poi-Ocular Cream

An in vitro skin penetration model using human cadaver skin mounted inFranz-type diffusion cells (FDC) was chosen to determine the skinpermeation of the compound of Formula I applied as a 2% cream to theepidermal surface. Transdermal flux into a receptor fluid was measuredover a period of 46 hours after application of the formulations. At theend of the 46-hour incubation period, the skin was tape-stripped andheat separated based on an established method and the concentration ofthe compound of Formula I was measured in the residual epidermis anddermis. The applied formulations comprised of 2% w/w compound of FormulaI, 46% w/w white petrolatum, 8% w/w mineral oil, 8% w/w propyleneglycol, 6.6% w/w ST-cyclomethicone-SNF, 3.3% w/w emulsifier 10, 2% w/wST-elastomer-10, 0.08% w/w methylparaben, 0.06% w/w sodium phosphatedibasic anhydrous, 0.05% w/w citric acid anhydrous, 0.02% w/wpropylparaben, and q.s. purified water. Vehicle cream comprised of 48%w/w white petrolatum, 8% w/w mineral oil, 8% w/w propylene glycol, 6.6%w/w ST-cyclomethicone-SNF, 3.3% w/w emulsifier 10, 2% w/wST-elastomer-10, 0.08% w/w methylparaben, 0.06% w/w sodium phosphatedibasic anhydrous, 0.05% w/w citric acid anhydrous, 0.02% w/wpropylparaben, and q.s. purified water was also tested as a negativecontrol.

Human cadaver skin from the posterior leg of a single donor, dermatomedto a thickness of approximately 250 82 m, was obtained from a commercialsource, cut into pieces of approximately 2 cm×2 cm with each such piecemounted in an FDC with a 0.55 cm² diffusional area and 3.3 mL receivervolume. The stratum corneum and the dermis were in contact with thedonor and receptor compartments, respectively. Following an integritycheck (impedance analysis), 10 μL of cream sample was applied to theepidermal surface of each FDC. An aliquot of the receptor fluid(comprised of phosphate-buffered saline pH 7.4 containing 0.01wt % Naazide and lwt% Brij 020) was sampled 4, 8, 24 and 46 hours afterapplication of test article and stored refrigerated until sampleanalysis. At the end of the 46-hour period, the epidermal surface ofeach skin sample was wiped clean, washed twice using 200 μL of a 1:1volume water/ethanol mixture. The skin was then tapped dry usingKimWipes, tape-stripped thrice with cellophane tape to remove theouter-most layers of the stratum corneum. The remaining skin was thensplit into epidermal and dermal compartments. The compound of Formula Iwas extracted with 3 mL of a 1:1 volume DMSO/isopropanol mixture at 40°C. for 24 hours.

A high performance liquid chromatography UV (“HPLC-UV”) analyticalmethod and an LC-MS/MS method for detecting the compound of Formula I inthe skin and in the receptor fluid samples, respectively, wasimplemented and employed mobile phases A (0.05 mL trifluoroacetic acid(TFA) in 1000 mL LC-MS grade water) and B (0.05 mL TFA in 1000 mL LC-MSgrade acetonitrile). The lower level of quantification (LLOQ) for thecompound of Formula I for the LC-MS/MS method was determined to be inthe 6-10 ng/mL range.

The accumulated amount of compound of Formula I in the epidermis anddermis and at each of the time points in the receptor fluid are shown inFIG. 5. A negative control using vehicle cream is also shown. Thecompound of Formula I was only detected in the epidermis, at 2.89+/−0.32μg/cm², and dermis, at 0.73+/−0.21 μg/cm², but not in the transdermalreceptor fluid. With the compound of Formula I being lipophilic with lowaqueous solubility (the solubility limit of the compound of Formula I inthe receptor fluid was determined to be approximately 35.8 μg/mL,sufficient to maintain sink conditions throughout the experiment), thedata very clearly demonstrate the much preferred partitioning of thecompound of Formula I into lipid containing compartments, such astissues, over hydrophilic compartments, such as the receptor fluid. Thischaracteristic most likely translates to lipid containing compartmentsin the eyelid in general, such as Meibomian glands, meibum, and otherfatty structures turning them into drug depot and “extended release”delivery mechanisms (via meibum) to the ocular surface for lipophiliccompounds administered peri-ocularly.

Example 4 Ocular and Systemic Exposure Following Peri-Ocular CreamAdministration

To determine the maximal tolerated dose amount first, two Hanfordminipigs were dosed twice-daily (BID) approximately 6 hours aparttopically with a cream (comprised of 2% w/w compound of Formula I, 46%w/w white petrolatum, 8% w/w mineral oil, 8% w/w propylene glycol, 6.6%w/w ST-cyclomethicone-SNF, 3.3% w/w emulsifier 10, 2% w/wST-elastomer-10, 0.08% w/w methylparaben, 0.06% w/w sodium phosphatedibasic anhydrous, 0.05% w/w citric acid anhydrous, 0.02% w/wpropylparaben, and q.s. purified water) to the upper and lower eyelidsof one eye, with ascending doses (25, 50, 75, 100 μL) over 4 days todetermine ocular and dermal tolerability and the maximal feasible amountof the cream formulation on each eyelid. Study variables assessed weremortality, clinical observations of illness or reaction to treatment,ocular observations using a modified Hackett McDonald grading system,and dermal Draize scoring. The cream was generally well tolerated at allfour doses administered BID. A dose amount of 75 μL per eyelid wasdetermined to be the maximal feasible dose amount, because of ease ofapplication and minimal risk of cream transfer to the ocular surface,which covered the entire minipig eyelid with a thin layer of the testarticle formulation with no dripping, flowing or running down of theformulation onto the ocular surface. The dose amount of 75 μL was thenused for subsequent studies.

To determine the ocular exposure and pharmacokinetics following topicalcream administration to the eyelids, the cream containing 2% of compoundof Formula I was applied BID to eyelids of 8 Hanford minipigs for 7 daysand one additional application on day 8 for a total of 15 topical doses.After the last dose on day 8, two animals each were euthanized at 2, 4,8, and 24 hours after the final dose, and eyes were collected fordissection into the following tissues and fluids: eyelids (includingpalpebral conjunctiva), bulbar conjunctiva, cornea, iris/ciliary body(ICB), and aqueous humor (AQH). Plasma was also collected (prior to doseapplication on Days 1 and 8, and prior to euthanasia). A decision wasmade not to attempt to collect meibum, since the amounts expressablefrom the lid margin were found to be minimal and the procedure of meibumexpression through manipulation/rubbing/squeezing of the eyelids wouldhave rendered the eyelid tissues compromised and unusable for furtheranalysis. Meibum was believed to be only one lipid compartment in theeyelids that could act as a depot for lipophilic compounds. Meibomianglands and other fatty tissues were others. Attempts to express meibumfrom the ducts, thereby rendering the eyelid itself unusable for furtheranalysis, would have not permitted assessment of drug content in otherpotential lipid structures in the eyelids. Thus, the decision was madeto assess drug exposure in the eyelid as an intact tissue to capture allpotential drug depots.

Three different extraction and analytical methods were developed for thedetermination of the compound of Formula I in i) plasma and aqueoushumor; ii) bulbar conjunctiva, cornea, ICB; iii) eyelids. Assay rangeswere 0.1-100 ng/mL, 1-1000 ng/g, and 1-1000 ng/g, respectively. Briefly,analytical methods were as follows: i) plasma and aqueous humorstandards were from minipig and rabbit, respectively; ii) bulbarconjunctiva, cornea, ICB standard was rabbit cornea; iii) eyelidstandard was pig skin. The internal standard working solution foranalytical purposes was comprised of 20.0 ng/mL ¹³C₂, ¹⁵N-labeledcompound of Formula I in acetonitrile with 1% formic acid (v/v) whichwas being added to each sample. The tissue/fluid sample extractionprocedure involved i) plasma/aqueous humor sample; ii) bulbarconjunctiva, cornea, ICB homogenization in acetonitrile; iii) eyeliddigestion in 1:1 acetonitrile:ammonium hydroxide solution for 1.5 hoursat 37° C. followed by acetonitrile addition, homogenization, andneutralization with formic acid; in all cases followed by addition ofinternal standard working solution, vortexing and centrifugation.Analysis of the samples was then carried out with LC-MS/MS, employingmobile phases A (Water with 0.1% formic acid) and B (acetonitrile with0.1% formic acid).

After 15 topical applications over 7.5 days, the highest ocular exposurelevels of the compound of Formula I after the final application weredetected in eyelid tissue (highest mean concentration of 30613 ng/g at 4hours post final dose), followed by bulbar conjunctiva (mean of 1931ng/g at 4 hours post final dose), cornea (mean of 452 ng/g at 8 hourspost final dose), ICB (mean of 20.48 ng/g at 24 hours post final dose),and aqueous humor (mean of 5.81 ng/g at 8 hours post final dose) (FIG.6). In all tissues, these concentration ranges representpharmacologically active concentrations of the compound of Formula Ieven when taking high protein binding of approximately 99% into accountresulting in “free” drug concentrations that are approximately1/100^(th) of the total measured concentration. Unexpectedly, in eachcompartment the exposure levels remained almost constant for up to 24hours post final peri-ocular dose application. This exposure profile isvery different from that of a typical eyedrop application and highlysuggestive of a drug depot in the eyelids that “feeds” the downstreamcompartments (conjunctiva, cornea, ICB, aqueous humor) over at least a24-hour period. Since lipophilic compounds preferentially partition intolipid compartments and not into aqueous, hydrophilic compartments asevidenced for the compound of Formula I by the aforementioned skinpermeation study it can be concluded that the lipid structures of theeyelid (e.g., meibomian glands, meibum, other fatty tissues) serve asdrug depots for peri-ocularly delivered drugs with the meibum becoming adrug delivery vehicle since it is constantly produced by the meibomianglands and secreted onto the corneal surface. These conclusions arerelated to, and consistent with, the lipophilic properties of thecompound of Formula I and, as such, are expected to generally translateto all other lipophilic compounds similarly if not equally.

Furthermore, this 24-hour exposure profile following peri-ocularadministration of a lipophilic compound, such as the compound of FormulaI, translates to a once-daily application regimen representing a majorbenefit for patients who are often required to administer steroid orother eyedrops up to 4 to 6 or more times each day. A once-dailyapplication regimen provides for improved safety and convenience forpatients over eyedrops that have to be administered more frequently.

A further significant benefit of peri-ocular application is the largerdosing volume which allows much greater flexibility with respect todelivery of a wide range of drug doses compared to eyedrop application,making it possible that many more drugs may be applied once-daily thanwith eyedrops, translating to the aforementioned patient benefit. Thevolume of eyedrops is typically limited to approximately a 30 μL volume,or up to approximately a 40 μL volume in some cases, per administrationper eye. A 75 μL peri-ocular dosing volume for each eyelid, or 150 μLper eye, equates to at least a 4-fold greater dose volume peradministration.

Yet a further benefit of pen-ocular application, aside from the largerdosing volume as described above, is that a greater percentage of drugis available for delivery to the target tissues at the ocular surface.Eyedrop application is particularly known for delivering only a smallfraction of the API that is applied as part of the eyedrop formulation.The reason is that an eyedrop applied to the ocular surface rapidlydrains away from the ocular surface via the nasolacrimal duct and isthus understood to deliver only about up to 1% of its API “payload”contained in the delivered eyedrop to the ocular surface tissues (corneaand conjunctiva). In contrast, pen-ocular administration deliversessentially 100% or close to 100% of the API contained in the pen-ocularformulation to the eyelid tissue. Taken together with the largerdelivery volume of a peri-ocularly applied formulation compared to atopically applied eyedrop, the peri-ocular route represents an enormousdosing advantage of API to ocular surface tissues over the topicaleyedrop route.

Plasma exposure to the compound of Formula I in this study (for up to 24hours after the last pen-ocular application) was variable but generallylow or below the lower limit of quantification of 0.1 ng/mL (FIG. 6).The highest plasma concentration, 2.22 ng/mL, was observed 24 hoursfollowing the final Day 8 dose. The results indicated that there was noor very low systemic accumulation after 7.5 days of multiple topicaleyelid application.

Plasma exposure was also determined in another 7-day study in minipigs.The compound of Formula I was formulated in a cream at 4% w/w and 6% w/wadditionally comprised of 44% w/w or 42% w/w White Petrolatum,respectively, and 8% w/w mineral oil, 8% w/w propylene glycol, 6.6% w/wST-cyclomethicone-SNF, 3.3% w/w emulsifier 10, 2% w/w ST-elastomer-10,0.08% w/w methylparaben, 0.06% w/w sodium phosphate dibasic anhydrous,0.05% w/w citric acid anhydrous, 0.02% w/w propylparaben, and q.s.purified water. The cream formulation was applied peri-ocularly at adose volume of 75 μL per eyelid to the upper and lower eyelids of theright eye of 3 minipigs for each concentration 3 times daily (TID) at an8-hour interval for 6 days and once in the morning on day 7. Plasmaslevels of the compound of Formula I were then assessed for up to 7 dayspost final dosing.

Dermal administration of 4% (18 mg/eye/day) and 6% (27 mg/eye/day)compound of Formula I cream to the upper and lower eyelids of one eye ofHanford minipigs was well tolerated. There were no test article-relatedeffects on body weights, clinical observations, tonometry (intraocularpressure), hematology, or serum chemistry.

In female minipigs receiving multiple doses of compound of Formula Icream at 18 mg/eye/day and 27 mg/eye/day, plasma TK parameters (C_(max),T_(max), AUC_(last), AUC₀₋₂₄) for the compound of Formula I were low andvariable. Plasma concentrations persisted for at least 2 to 7 days afterthe last administered dose.

This is an intriguing and unexpected finding as the data suggest thatthe ocular drug depot (established following peri-ocular creamapplication for 7 days) released drug over an extended period of timesuch that, in some animals, systemic levels of the compound of Formula Icould be measured for up to 7 days after the final peri-ocular creamapplication. Conceptually, these finding are entirely consistent withextended delivery from a Meibomian gland/meibum drug depot to thesystemic circulation and, presumably, ocular surface.

Example 5 Manufacturing Process

Pen-ocular application requires a sterile manufacturing process forophthalmic drug products, regardless of the presence or absence ofpreservatives in the formulation. The manufacturing process, as outlinedin FIG. 7, is based on the combination under aseptic conditions ofhydrophilic and lipophilic components, each presterilized separately byan appropriate sterilization process, such as filtration, heat, gamma orbeta or alpha irradiation, or otherwise. The presterilized API (heat,gamma or beta or alpha irradiation, or otherwise) is incorporated intothe presterilized lipophilic component at an appropriate temperatureusing an appropriate mixing process. Then, this lipophilic component ismixed with the presterilized hydrophilic component at an appropriatetemperature using an appropriate process, such as stirring, shaking,vortexing, sonication, etc. at a predetermined mixing rate. The finalmixture is then allowed to cool to an appropriate temperature necessaryfor the filling process into appropriate containers for the final drugproduct, whether for clinical or commercial use.

As one embodiment, the manufacturing process of a cream comprising thecompound of Formula I, as described in this application and in FIG. 7,requires a high-speed homogenization procedure to incorporate the APIand a gentle mixing/stirring procedure for combining the lipophilic andhydrophilic components. In the same embodiment, the lipophilic componentis heated to 55-60° C. for the incorporation of the API, such as thecompound of Formula I, and the mixing process with the hydrophiliccomponent. The final product is then slowly cooled to under 30° C. priorto filling into the final containers for a clinical study or commercialuse.

In other embodiments, the lipophilic component is heated to atemperature necessary to liquefy this component to make it suitable to asterilization procedure by filtration, or not heated at all. Thisincludes temperature ranges of 1-10° C., 10-20° C., 20-30° C., 30-40°C., 40-50° C., 50-60° C., 60-70° C., 70-80° C., 80-90° C., 90-100° C.,100-110° C., 110-120° C., 120-130° C., 130-140° C., 140-150° C.,150-160° C., and 160-170° C.

In other embodiments, incorporation of the API requires a slow, high, orintermediate mixing speed at a specific temperature within a range of1-10° C., 10-20° C., 20-30° C., 30-40° C., 40-50° C., 50-60° C., 60-70°C., 70-80° C., 80-90° C., 90-100° C., 100-110° C., 110-120° C., 120-130°C., 130-140° C., 140-150° C., 150-160° C., and 160-170° C. This processincludes mixing, shaking, stirring, vortexing, sonication, etc.

In other embodiments, mixing of the hydrophilic and lipophiliccomponents is achieved at room temperature or temperature ranges of1-10° C., 10-20° C., 20-30° C., 30-40° C., 40-50° C., 50-60° C., 60-70°C., 70-80° C., 80-90° C., 90-100° C., 100-110° C., 110-120° C., 120-130°C., 130-140° C., 140-150° C., 150-160° C., and 160-170° C.

In other embodiments, the final product is then slowly or rapidly cooledto a temperature necessary for the filling into the final containers fora clinical study or commercial use. This cooling process requires mixingat a slow, rapid or intermediate speed, or no mixing at all.

What is claimed is:
 1. A pharmaceutical composition comprising: a) atherapeutically effective amount of a steroid; and b) a pharmaceuticallyacceptable carrier adapted for peri-ocular transdermal delivery of thesteroid to one or more pen-orbital glands of a subject; wherein thepharmaceutical composition is specifically formulated for peri-oculardelivery.
 2. The pharmaceutical composition of claim 1, wherein thesteroid is selected from the group consisting of a compound of FormulaI, fluocinolone, difluprednate, fluticasone, fluorometholone,loteprednol, dexamethasone, prednisolone, triamcinolone acetonide,rimexolone, cortisol, cortisone, hydrocortisone, testosterone, and esterderivatives thereof; wherein the compound of Formula I comprises thestructure:


3. The pharmaceutical composition of claim 2, wherein the steroid is thecompound of Formula I.
 4. The pharmaceutical composition of claim 1,wherein the pharmaceutical composition comprises the steroid at aconcentration between about 0.001% and about 10% weight per weight(w/w).
 5. The pharmaceutical composition of claim 4, wherein thepharmaceutical composition comprises the steroid at a concentration ofabout 2% w/w.
 6. The pharmaceutical composition of claim 1, wherein thepharmaceutically acceptable carrier is selected from the groupconsisting of an ointment, cream, lotion, gel, emulsion, suspension,oil, foam, transdermal patch, spray, and any combinations thereof. 7.The pharmaceutical composition of claim 6, wherein the cream comprisesan oil-in-water base or a water-in-oil base.
 8. The pharmaceuticalcomposition of claim 6, wherein the cream comprises white petrolatum,mineral oil, propylene glycol, ST-cyclomethicone-SNF, emulsifier 10,ST-elastomer-10, sodium phosphate dibasic anhydrous, citric acid, andpurified water.
 9. The pharmaceutical composition of claim 8, whereinthe cream comprises the steroid at a concentration of about 2% w/w, 46%w/w white petrolatum, 8% w/w mineral oil, 8% w/w propylene glycol, 6.6%w/w ST-cyclomethicone-SNF, 3.3% w/w emulsifier 10, 2% w/wST-elastomer-10, 0.06% w/w sodium phosphate dibasic anhydrous, 0.05% w/wcitric acid anhydrous, and purified water.
 10. The pharmaceuticalcomposition of claim 8, wherein the cream further comprises benzalkoniumchloride (BAK), or propylparaben and methylparaben.
 11. Thepharmaceutical composition of claim 1, wherein the subject is a human ora non-human animal.
 12. The pharmaceutical composition of claim 1,wherein the subject suffers from an ocular disease.
 13. Thepharmaceutical composition of claim 12, wherein the ocular disease isselected from the group consisting of inflammation of the peri-ocularglands, meibomitis, dry eye disease, allergic eye disease, topicalpreservative toxicity, xerophthalmia, loss of homeostasis of the tearfilm, tear film instability and hyperosmolarity, ocular surfaceinflammation and damage, neuronal sensory abnormalities, Meibomian glanddysfunction, exacerbated inflammatory ocular surface disease,phlyctenular keratitis, chalazion, anterior blepharitis, posteriorblepharitis, and any combinations thereof.
 14. A method of providingprophylactic, palliative, or therapeutic relief of one or more signs orsymptoms of an ocular disease in a subject, comprising administering tothe subject a pharmaceutical composition comprising: a) atherapeutically effective amount of a steroid; and b) a pharmaceuticallyacceptable carrier adapted for peri-ocular transdermal delivery of thesteroid to one or more pen-orbital glands of a subject; wherein thepharmaceutical composition is specifically formulated for pen-oculardelivery.
 15. The method of claim 14, wherein the pharmaceuticalcomposition is topically administered to the external portion of anupper and/or lower eyelid of the subject.
 16. The method of claim 14,wherein the steroid is delivered to an ocular surface of the subject viathe Meibomian gland.
 17. The method of claim 14, wherein the one or moreperi-orbital glands are selected from the group consisting of aMeibomian gland, a lacrimal gland, an accessory lacrimal gland, and anycombinations thereof.
 18. The method of claim 14, wherein the steroid isselected from the group consisting of a compound of Formula I,fluocinolone, difluprednate, fluticasone, fluorometholone, loteprednol,dexamethasone, prednisolone, triamcinolone acetonide, rimexolone,cortisol, cortisone, hydrocortisone, testosterone, and ester derivativesthereof; wherein the compound of Formula I comprises the structure:


19. The method of claim 18, wherein the steroid is the compound ofFormula I.
 20. The method of claim 14, wherein the pharmaceuticalcomposition comprises the steroid at a concentration between about0.001% and about 10% weight per weight (w/w).
 21. The method of claim20, wherein the pharmaceutical composition comprises the steroid at aconcentration of about 2% w/w.
 22. The method of claim 14, wherein thepharmaceutically acceptable carrier is selected from the groupconsisting of an ointment, cream, lotion, gel, emulsion, suspension,oil, foam, transdermal patch, spray, and any combinations thereof. 23.The method of claim 22, wherein the cream comprises an oil-in-water baseor a water-in-oil base.
 24. The pharmaceutical composition of claim 22,wherein the cream comprises white petrolatum, mineral oil, propyleneglycol, ST-cyclomethicone-SNF, emulsifier 10, ST-elastomer-10, sodiumphosphate dibasic anhydrous, citric acid, and purified water.
 25. Themethod of claim 24, wherein the cream comprises the steroid at aconcentration of about 2% w/w, 46% w/w white petrolatum, 8% w/w mineraloil, 8% w/w propylene glycol, 6.6% w/w ST-cyclomethicone-SNF, 3.3% w/wemulsifier 10, 2% w/w ST-elastomer-10, 0.06% w/w sodium phosphatedibasic anhydrous, 0.05% w/w citric acid anhydrous, and purified water.26. The method of claim 24, wherein the cream further comprisesbenzalkonium chloride (BAK), or propylparaben and methylparaben.
 27. Themethod of claim 14, wherein the pharmaceutical composition isadministered one, two, three, four, five, six or more times per day. 28.The method of claim 14, wherein the pharmaceutical composition isadministered for one day, two days, three days, four days, five days,six days, one week, two weeks, three weeks, four weeks, five weeks, sixweeks, seven weeks, eight weeks, nine weeks, 10 weeks, 11 weeks, 12weeks or more, 24 weeks, 36 weeks, 48 weeks or more.
 29. The method ofclaim 14, wherein the subject is a human or a non-human animal.
 30. Themethod of claim 14, wherein the ocular disease is selected from thegroup consisting of inflammation of the peri-ocular glands, meibomitis,dry eye disease, allergic eye disease, topical preservative toxicity,xerophthalmia, loss of homeostasis of the tear film, tear filminstability and hyperosmolarity, ocular surface inflammation and damage,neuronal sensory abnormalities, Meibomian gland dysfunction, exacerbatedinflammatory ocular surface disease, phlyctenular keratitis, chalazion,anterior blepharitis, posterior blepharitis, and any combinationsthereof.